Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID
Abstract
:1. Introduction
2. Long COVID Pathogenesis Is Unknown
Role of SARS-CoV-2 S Protein in the Nervous System Damage
3. Microglia-Induced Neuroinflammation and Mental Health
4. Microglia Communicate with Mast Cells
5. Mast Cells in the CNS
6. Mast Cells in Long COVID
7. Neuroimmune Biomarkers
8. Lack of Effective Treatments
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ACE2 | Angiotensin-converting enzyme 2 |
Apoe4 | Apolipoprotein E4 |
BBB | Blood–brain barrier |
CNS | Central nervous system |
CSF | Cerebrospinal fluid |
CXCL8 | Chemokine (C-X-C motif) ligand 8 |
COVID-19 | Coronavirus disease-2019 |
CRH | Corticotropin-releasing hormone |
DAMPs | Damage-associated molecular patterns (DAMPs) |
GFAP | Glial fibrillary acidic protein |
HK-1 | Hemokinin-1 |
HLA | Human leukocyte antigen |
Iba1 | Calcium-binding adapter molecule 1 |
IL-1β | Interleukin-1 beta |
LPS | Lipopolysaccharide |
MMCP6, 7 | Mast cell proteases 6 and 7 |
MAP-2 | Microtubule-associated protein-2 |
MCI | Mild cognitive impairment |
mtDNA | Mitochondrial DNA |
MS | Multiple sclerosis |
NGF | Nerve growth factor |
NfL | Neurofilament light chain |
NK-1 | Neurokinin-1 |
NLGs | Neuroligins |
NT | Neurotensin |
NSAIDs | Non-steroidal anti-inflammatory drugs |
NF-κB | Nuclear factor kappa B |
NLRP3 | Nucleotide-binding domain (NOD)-like receptor protein 3 |
PAMPs | Pathogen-associated molecular patterns |
PD | Parkinson’s disease |
PASC | Post-acute sequelae of SARS-CoV-2 |
PTSD | Post-traumatic stress disorder |
S | Spike |
SARS-CoV-3 | Severe Acute respiratory syndrome coronavirus 2 |
SP | Substance P |
TLRs | Toll-like receptors |
TNF | Tumor necrosis factor |
References
- Brodin, P. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 2021, 27, 28–33. [Google Scholar] [CrossRef]
- Asadi, S.; Alysandratos, K.D.; Angelidou, A.; Miniati, A.; Sismanopoulos, N.; Vasiadi, M.; Zhang, B.; Kalogeromitros, D.; Theoharides, T.C. Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells. J. Investig. Dermatol. 2012, 132, 324–329. [Google Scholar] [CrossRef] [Green Version]
- Canna, S.W.; Cron, R.Q. Highways to hell: Mechanism-based management of cytokine storm syndromes. J. Allergy Clin. Immunol. 2020, 146, 949–959. [Google Scholar] [CrossRef]
- Giamarellos-Bourboulis, E.J.; Netea, M.G.; Rovina, N.; Akinosoglou, K.; Antoniadou, A.; Antonakos, N.; Damoraki, G.; Gkavogianni, T.; Adami, M.E.; Katsaounou, P.; et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe 2020, 27, 992–1000.e1003. [Google Scholar] [CrossRef]
- Ye, Q.; Wang, B.; Mao, J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J. Infect. 2020, 80, 607–613. [Google Scholar] [CrossRef]
- Chen, G.; Wu, D.; Guo, W.; Cao, Y.; Huang, D.; Wang, H.; Wang, T.; Zhang, X.; Chen, H.; Yu, H.; et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig. 2020, 130, 2620–2629. [Google Scholar] [CrossRef] [Green Version]
- Paces, J.; Strizova, Z.; Smrz, D.; Cerny, J. COVID-19 and the immune system. Physiol. Res. 2020, 69, 379–388. [Google Scholar] [CrossRef]
- Ragab, D.; Salah Eldin, H.; Taeimah, M.; Khattab, R.; Salem, R. The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 2020, 11, 1446. [Google Scholar] [CrossRef]
- Copaescu, A.; Smibert, O.; Gibson, A.; Phillips, E.J.; Trubiano, J.A. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. J. Allergy Clin. Immunol. 2020, 146, 518–534.e511. [Google Scholar] [CrossRef]
- Moore, J.B.; June, C.H. Cytokine release syndrome in severe COVID-19. Science 2020, 368, 473–474. [Google Scholar] [CrossRef] [Green Version]
- Herold, T.; Jurinovic, V.; Arnreich, C.; Lipworth, B.J.; Hellmuth, J.C.; von Bergwelt-Baildon, M.; Klein, M.; Weinberger, T. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J. Allergy Clin. Immunol. 2020, 146, 128–136.e124. [Google Scholar] [CrossRef]
- Proal, A.D.; VanElzakker, M.B. Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol. 2021, 12, 698169. [Google Scholar] [CrossRef]
- Dotan, A.; Shoenfeld, Y. Post-COVID syndrome: The aftershock of SARS-CoV-2. Int. J. Infect. Dis. 2022, 114, 233–235. [Google Scholar] [CrossRef]
- O’Mahoney, L.L.; Routen, A.; Gillies, C.; Ekezie, W.; Welford, A.; Zhang, A.; Karamchandani, U.; Simms-Williams, N.; Cassambai, S.; Ardavani, A.; et al. The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine 2023, 55, 101762. [Google Scholar] [CrossRef]
- Ceban, F.; Ling, S.; Lui, L.M.W.; Lee, Y.; Gill, H.; Teopiz, K.M.; Rodrigues, N.B.; Subramaniapillai, M.; Di Vincenzo, J.D.; Cao, B.; et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav. Immun. 2022, 101, 93–135. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Conti, P. COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome? J. Biol. Regul. Homeost. Agents 2020, 34, 1633–1636. [Google Scholar] [CrossRef]
- Theoharides, T.C. Potential association of mast cells with coronavirus disease 2019. Ann. Allergy Asthma Immunol. 2021, 126, 217–218. [Google Scholar] [CrossRef]
- Theoharides, T.C. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors 2020, 46, 306–308. [Google Scholar] [CrossRef]
- Townsend, L.; Dyer, A.H.; Jones, K.; Dunne, J.; Mooney, A.; Gaffney, F.; O’Connor, L.; Leavy, D.; O’Brien, K.; Dowds, J.; et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE 2020, 15, e0240784. [Google Scholar] [CrossRef]
- Weinstock, L.B.; Brook, J.B.; Walters, A.S.; Goris, A.; Afrin, L.B.; Molderings, G.J. Mast cell activation symptoms are prevalent in Long-COVID. Int. J. Infect. Dis. 2021, 112, 217–226. [Google Scholar] [CrossRef]
- Ongur, D.; Perlis, R.; Goff, D. Psychiatry and COVID-19. JAMA 2020, 324, 1149–1150. [Google Scholar] [CrossRef]
- Vindegaard, N.; Benros, M.E. COVID-19 pandemic and mental health consequences: Systematic review of the current evidence. Brain Behav. Immun. 2020, 89, 531–542. [Google Scholar] [CrossRef]
- Pfefferbaum, B.; North, C.S. Mental Health and the COVID-19 Pandemic. N. Engl. J. Med. 2020, 383, 510–512. [Google Scholar] [CrossRef]
- Xiang, Y.T.; Yang, Y.; Li, W.; Zhang, L.; Zhang, Q.; Cheung, T.; Ng, C.H. Timely mental health care for the 2019 novel coronavirus outbreak is urgently needed. Lancet Psychiatry 2020, 7, 228–229. [Google Scholar] [CrossRef] [Green Version]
- Efstathiou, V.; Stefanou, M.I.; Demetriou, M.; Siafakas, N.; Makris, M.; Tsivgoulis, G.; Zoumpourlis, V.; Kympouropoulos, S.P.; Tsoporis, J.N.; Spandidos, D.A.; et al. Long COVID and neuropsychiatric manifestations (Review). Exp. Ther. Med. 2022, 23, 363. [Google Scholar] [CrossRef]
- Badenoch, J.B.; Rengasamy, E.R.; Watson, C.; Jansen, K.; Chakraborty, S.; Sundaram, R.D.; Hafeez, D.; Burchill, E.; Saini, A.; Thomas, L.; et al. Persistent neuropsychiatric symptoms after COVID-19: A systematic review and meta-analysis. Brain Commun. 2022, 4, fcab297. [Google Scholar] [CrossRef]
- Han, Y.; Yuan, K.; Wang, Z.; Liu, W.J.; Lu, Z.A.; Liu, L.; Shi, L.; Yan, W.; Yuan, J.L.; Li, J.L.; et al. Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Transl. Psychiatry 2021, 11, 499. [Google Scholar] [CrossRef]
- Polyzoidis, S.; Koletsa, T.; Panagiotidou, S.; Ashkan, K.; Theoharides, T.C. Mast cells in meningiomas and brain inflammation. J. Neuroinflamm. 2015, 12, 170. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C. Mast cells: The immune gate to the brain. Life Sci. 1990, 46, 607–617. [Google Scholar] [CrossRef]
- Zhou, Q.; Wang, Y.W.; Ni, P.F.; Chen, Y.N.; Dong, H.Q.; Qian, Y.N. Effect of tryptase on mouse brain microvascular endothelial cells via protease-activated receptor 2. J. Neuroinflamm. 2018, 15, 248. [Google Scholar] [CrossRef] [Green Version]
- Novak, P.; Giannetti, M.P.; Weller, E.; Hamilton, M.J.; Castells, M. Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy. Ann. Allergy Asthma Immunol. 2022, 128, 299–306. [Google Scholar] [CrossRef]
- Sandhu, J.K.; Kulka, M. Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int. J. Mol. Sci. 2021, 22, 1093. [Google Scholar] [CrossRef]
- Skaper, S.D.; Facci, L.; Giusti, P. Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: A review. CNS Neurol. Disord. Drug Targets 2014, 13, 1654–1666. [Google Scholar] [CrossRef]
- Cron, R.Q.; Goyal, G.; Chatham, W.W. Cytokine Storm Syndrome. Annu. Rev. Med. 2022, 74, 321–337. [Google Scholar] [CrossRef]
- Dutta, D.; Liu, J.; Xiong, H. NLRP3 inflammasome activation and SARS-CoV-2-mediated hyperinflammation, cytokine storm and neurological syndromes. Int. J. Physiol. Pathophysiol. Pharmacol. 2022, 14, 138–160. [Google Scholar]
- Rasool, G.; Riaz, M.; Abbas, M.; Fatima, H.; Qamar, M.M.; Zafar, F.; Mahmood, Z. COVID-19: Clinical laboratory diagnosis and monitoring of novel coronavirus infected patients using molecular, serological and biochemical markers: A review. Int. J. Immunopathol. Pharmacol. 2022, 36, 3946320221115316. [Google Scholar] [CrossRef]
- Long COVID: Let patients help define long-lasting COVID symptoms. Nature 2020, 586, 170. [CrossRef]
- Spudich, S.; Nath, A. Nervous system consequences of COVID-19. Science 2022, 375, 267–269. [Google Scholar] [CrossRef]
- Finsterer, J.; Scorza, F.A. Clinical and Pathophysiologic Spectrum of Neuro-COVID. Mol. Neurobiol. 2021, 58, 3787–3791. [Google Scholar] [CrossRef]
- Davies, D.A.; Adlimoghaddam, A.; Albensi, B.C. The Effect of COVID-19 on NF-kappaB and Neurological Manifestations of Disease. Mol. Neurobiol. 2021, 58, 4178–4187. [Google Scholar] [CrossRef]
- Norouzi, M.; Miar, P.; Norouzi, S.; Nikpour, P. Nervous System Involvement in COVID-19: A Review of the Current Knowledge. Mol. Neurobiol. 2021, 58, 3561–3574. [Google Scholar] [CrossRef]
- Dewanjee, S.; Vallamkondu, J.; Kalra, R.S.; Puvvada, N.; Kandimalla, R.; Reddy, P.H. Emerging COVID-19 Neurological Manifestations: Present Outlook and Potential Neurological Challenges in COVID-19 Pandemic. Mol. Neurobiol. 2021, 58, 4694–4715. [Google Scholar] [CrossRef]
- Patel, M.A.; Knauer, M.J.; Nicholson, M.; Daley, M.; Van Nynatten, L.R.; Martin, C.; Patterson, E.K.; Cepinskas, G.; Seney, S.L.; Dobretzberger, V.; et al. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol. Med. 2022, 28, 122. [Google Scholar] [CrossRef]
- Schou, T.M.; Joca, S.; Wegener, G.; Bay-Richter, C. Psychiatric and neuropsychiatric sequelae of COVID-19—A systematic review. Brain Behav. Immun. 2021, 97, 328–348. [Google Scholar] [CrossRef]
- Vikse, J.; Omdal, R. Fatigue in Mastocytosis: A Case Series. Clin. Ther. 2019, 41, 625–632. [Google Scholar] [CrossRef] [Green Version]
- Georgin-Lavialle, S.; Gaillard, R.; Moura, D.; Hermine, O. Mastocytosis in adulthood and neuropsychiatric disorders. Transl. Res. 2016, 174, 77–85.e71. [Google Scholar] [CrossRef]
- Afrin, L.B.; Pohlau, D.; Raithel, M.; Haenisch, B.; Dumoulin, F.L.; Homann, J.; Mauer, U.M.; Harzer, S.; Molderings, G.J. Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases. Brain Behav. Immun. 2015, 50, 314–321. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Cholevas, C.; Polyzoidis, K.; Politis, A. Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue. Biofactors 2021, 47, 232–241. [Google Scholar] [CrossRef]
- Hatziagelaki, E.; Adamaki, M.; Tsilioni, I.; Dimitriadis, G.; Theoharides, T.C. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus? J. Pharmacol. Exp. Ther. 2018, 367, 155–167. [Google Scholar] [CrossRef] [Green Version]
- Sukocheva, O.A.; Maksoud, R.; Beeraka, N.M.; Madhunapantula, S.V.; Sinelnikov, M.; Nikolenko, V.N.; Neganova, M.E.; Klochkov, S.G.; Amjad Kamal, M.; Staines, D.R.; et al. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome. J. Adv. Res. 2022, 40, 179–196. [Google Scholar] [CrossRef]
- Kempuraj, D.; Selvakumar, G.P.; Thangavel, R.; Ahmed, M.E.; Zaheer, S.; Kumar, K.K.; Yelam, A.; Kaur, H.; Dubova, I.; Raikwar, S.P.; et al. Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation. J. Alzheimers Dis. 2018, 66, 1117–1129. [Google Scholar] [CrossRef]
- Liu, S.; Suzuki, Y.; Takemasa, E.; Watanabe, R.; Mogi, M. Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex. Eur. J. Pharmacol. 2022, 930, 175169. [Google Scholar] [CrossRef]
- Arun, S.; Storan, A.; Myers, B. Mast cell activation syndrome and the link with long COVID. Br. J. Hosp. Med. 2022, 83, 1–10. [Google Scholar] [CrossRef]
- Murdaca, G.; Di Gioacchino, M.; Greco, M.; Borro, M.; Paladin, F.; Petrarca, C.; Gangemi, S. Basophils and Mast Cells in COVID-19 Pathogenesis. Cells 2021, 10, 2754. [Google Scholar] [CrossRef]
- Afrin, L.B.; Weinstock, L.B.; Molderings, G.J. COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in mast cell activation syndrome. Int. J. Infect. Dis. 2020, 100, 327–332. [Google Scholar] [CrossRef]
- Ozdemir, O.; Goksu Erol, A.Y.; Dikici, U. Mast Cell’s Role in Cytokine Release Syndrome and Related Manifestations of COVID-19 Disease. Curr. Pharm. Des. 2022, 28, 3261–3268. [Google Scholar] [CrossRef]
- Hafezi, B.; Chan, L.; Knapp, J.P.; Karimi, N.; Alizadeh, K.; Mehrani, Y.; Bridle, B.W.; Karimi, K. Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells. Cells 2021, 10, 1761. [Google Scholar] [CrossRef]
- Phillips, S.; Williams, M.A. Confronting Our Next National Health Disaster—Long-Haul Covid. N. Engl. J. Med. 2021, 385, 577–579. [Google Scholar] [CrossRef]
- Your Health, Your Money. In Long Covid May Be “The Next Public Health Disaster”—With a $3.7 Trillion Economic Impact Rivaline the Great Recession; Iacurci, G. (Ed.) CNBC: Englewood Cliffs, NJ, USA, 2022. [Google Scholar]
- Tremblay, M.E.; Madore, C.; Bordeleau, M.; Tian, L.; Verkhratsky, A. Neuropathobiology of COVID-19: The Role for Glia. Front. Cell. Neurosci. 2020, 14, 592214. [Google Scholar] [CrossRef]
- McMahon, C.L.; Staples, H.; Gazi, M.; Carrion, R.; Hsieh, J. SARS-CoV-2 targets glial cells in human cortical organoids. Stem Cell Rep. 2021, 16, 1156–1164. [Google Scholar] [CrossRef]
- Butowt, R.; von Bartheld, C.S. The route of SARS-CoV-2 to brain infection: Have we been barking up the wrong tree? Mol. Neurodegener. 2022, 17, 20. [Google Scholar] [CrossRef]
- Tai, W.; He, L.; Zhang, X.; Pu, J.; Voronin, D.; Jiang, S.; Zhou, Y.; Du, L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol. Immunol. 2020, 17, 613–620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Espindola, O.M.; Gomes, Y.C.P.; Brandao, C.O.; Torres, R.C.; Siqueira, M.; Soares, C.N.; Lima, M.; Leite, A.; Venturotti, C.O.; Carvalho, A.J.C.; et al. Inflammatory Cytokine Patterns Associated with Neurological Diseases in Coronavirus Disease 2019. Ann. Neurol. 2021, 89, 1041–1045. [Google Scholar] [CrossRef]
- Oka, Y.; Ueda, A.; Nakagawa, T.; Kikuchi, Y.; Inoue, D.; Marumo, S.; Matsumoto, S. SARS-CoV-2-related Progressive Brain White Matter Lesion Associated with an Increased Cerebrospinal Fluid Level of IL-6. Intern. Med. 2021, 60, 3167–3170. [Google Scholar] [CrossRef]
- Meinhardt, J.; Radke, J.; Dittmayer, C.; Franz, J.; Thomas, C.; Mothes, R.; Laue, M.; Schneider, J.; Brunink, S.; Greuel, S.; et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat. Neurosci. 2021, 24, 168–175. [Google Scholar] [CrossRef]
- Jiao, L.; Yang, Y.; Yu, W.; Zhao, Y.; Long, H.; Gao, J.; Ding, K.; Ma, C.; Li, J.; Zhao, S.; et al. The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys. Signal Transduct. Target. Ther. 2021, 6, 169. [Google Scholar] [CrossRef]
- Gomes, I.; Karmirian, K.; Oliveira, J.T.; Pedrosa, C.; Mendes, M.A.; Rosman, F.C.; Chimelli, L.; Rehen, S. SARS-CoV-2 infection of the central nervous system in a 14-month-old child: A case report of a complete autopsy. Lancet Reg. Health Am. 2021, 2, 100046. [Google Scholar] [CrossRef]
- Yang, A.C.; Kern, F.; Losada, P.M.; Agam, M.R.; Maat, C.A.; Schmartz, G.P.; Fehlmann, T.; Stein, J.A.; Schaum, N.; Lee, D.P.; et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 2021, 595, 565–571. [Google Scholar] [CrossRef]
- Brann, D.H.; Tsukahara, T.; Weinreb, C.; Lipovsek, M.; Van den Berge, K.; Gong, B.; Chance, R.; Macaulay, I.C.; Chou, H.J.; Fletcher, R.B.; et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci. Adv. 2020, 6, eabc5801. [Google Scholar] [CrossRef]
- Xu, J.; Zhong, S.; Liu, J.; Li, L.; Li, Y.; Wu, X.; Li, Z.; Deng, P.; Zhang, J.; Zhong, N.; et al. Detection of severe acute respiratory syndrome coronavirus in the brain: Potential role of the chemokine mig in pathogenesis. Clin. Infect. Dis. 2005, 41, 1089–1096. [Google Scholar] [CrossRef] [Green Version]
- Karnik, M.; Beeraka, N.M.; Uthaiah, C.A.; Nataraj, S.M.; Bettadapura, A.D.S.; Aliev, G.; Madhunapantula, S.V. A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development. Mol. Neurobiol. 2021, 58, 4535–4563. [Google Scholar] [CrossRef]
- Sodagar, A.; Javed, R.; Tahir, H.; Razak, S.I.A.; Shakir, M.; Naeem, M.; Yusof, A.H.A.; Sagadevan, S.; Hazafa, A.; Uddin, J.; et al. Pathological Features and Neuroinflammatory Mechanisms of SARS-CoV-2 in the Brain and Potential Therapeutic Approaches. Biomolecules 2022, 12, 971. [Google Scholar] [CrossRef]
- Tremblay, M.E.; Madore, C.; Tian, L.; Verkhratsky, A. Editorial: Role of Neuroinflammation in the Neuropsychiatric and Neurological Aspects of COVID-19. Front. Cell. Neurosci. 2022, 16, 840121. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.H.; Perl, D.P.; Nair, G.; Li, W.; Maric, D.; Murray, H.; Dodd, S.J.; Koretsky, A.P.; Watts, J.A.; Cheung, V.; et al. Microvascular Injury in the Brains of Patients with COVID-19. N. Engl. J. Med. 2021, 384, 481–483. [Google Scholar] [CrossRef] [PubMed]
- Adesse, D.; Gladulich, L.; Alvarez-Rosa, L.; Siqueira, M.; Marcos, A.C.; Heider, M.; Motta, C.S.; Torices, S.; Toborek, M.; Stipursky, J. Role of aging in Blood-Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: Impacts on neurological symptoms of COVID-19. Fluids Barriers CNS 2022, 19, 63. [Google Scholar] [CrossRef]
- Bodnar, B.; Patel, K.; Ho, W.; Luo, J.J.; Hu, W. Cellular mechanisms underlying neurological/neuropsychiatric manifestations of COVID-19. J. Med. Virol. 2021, 93, 1983–1998. [Google Scholar] [CrossRef]
- Ng, J.H.; Sun, A.; Je, H.S.; Tan, E.K. Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids. Neuroscientist 2021, 29, 30–40. [Google Scholar] [CrossRef]
- Theoharides, T.C. Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome? Mol. Neurobiol. 2022, 59, 1850–1861. [Google Scholar] [CrossRef] [PubMed]
- Song, E.; Zhang, C.; Israelow, B.; Lu-Culligan, A.; Prado, A.V.; Skriabine, S.; Lu, P.; Weizman, O.E.; Liu, F.; Dai, Y.; et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 2021, 218, e20202135. [Google Scholar] [CrossRef]
- Veleri, S. Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients. Exp. Brain Res. 2022, 240, 9–25. [Google Scholar] [CrossRef]
- Cai, Y.; Zhang, J.; Xiao, T.; Peng, H.; Sterling, S.M.; Walsh, R.M., Jr.; Rawson, S.; Rits-Volloch, S.; Chen, B. Distinct conformational states of SARS-CoV-2 spike protein. Science 2020, 369, 1586–1592. [Google Scholar] [CrossRef] [PubMed]
- Jeong, G.U.; Lyu, J.; Kim, K.D.; Chung, Y.C.; Yoon, G.Y.; Lee, S.; Hwang, I.; Shin, W.H.; Ko, J.; Lee, J.Y.; et al. SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death. Microbiol. Spectr. 2022, 10, e0109122. [Google Scholar] [CrossRef] [PubMed]
- Olajide, O.A.; Iwuanyanwu, V.U.; Adegbola, O.D.; Al-Hindawi, A.A. SARS-CoV-2 Spike Glycoprotein S1 Induces Neuroinflammation in BV-2 Microglia. Mol. Neurobiol. 2022, 59, 445–458. [Google Scholar] [CrossRef] [PubMed]
- Samudyata; Oliveira, A.O.; Malwade, S.; Rufino de Sousa, N.; Goparaju, S.K.; Gracias, J.; Orhan, F.; Steponaviciute, L.; Schalling, M.; Sheridan, S.D.; et al. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol. Psychiatry 2022, 27, 3939–3950. [Google Scholar] [CrossRef]
- Frank, M.G.; Nguyen, K.H.; Ball, J.B.; Hopkins, S.; Kelley, T.; Baratta, M.V.; Fleshner, M.; Maier, S.F. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties. Brain Behav. Immun. 2022, 100, 267–277. [Google Scholar] [CrossRef]
- Savelieff, M.G.; Feldman, E.L.; Stino, A.M. Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection. Neurobiol. Dis. 2022, 168, 105715. [Google Scholar] [CrossRef]
- Kim, E.S.; Jeon, M.T.; Kim, K.S.; Lee, S.; Kim, S.; Kim, D.G. Spike Proteins of SARS-CoV-2 Induce Pathological Changes in Molecular Delivery and Metabolic Function in the Brain Endothelial Cells. Viruses 2021, 13, 2021. [Google Scholar] [CrossRef]
- Perico, L.; Morigi, M.; Galbusera, M.; Pezzotta, A.; Gastoldi, S.; Imberti, B.; Perna, A.; Ruggenenti, P.; Donadelli, R.; Benigni, A.; et al. SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation. Front. Immunol. 2022, 13, 827146. [Google Scholar] [CrossRef]
- Raghavan, S.; Leo, M.D. Histamine Potentiates SARS-CoV-2 Spike Protein Entry Into Endothelial Cells. Front. Pharmacol. 2022, 13, 872736. [Google Scholar] [CrossRef]
- Yang, R.C.; Huang, K.; Zhang, H.P.; Li, L.; Zhang, Y.F.; Tan, C.; Chen, H.C.; Jin, M.L.; Wang, X.R. SARS-CoV-2 productively infects human brain microvascular endothelial cells. J. Neuroinflamm. 2022, 19, 149. [Google Scholar] [CrossRef]
- Erickson, M.A.; Rhea, E.M.; Knopp, R.C.; Banks, W.A. Interactions of SARS-CoV-2 with the Blood-Brain Barrier. Int. J. Mol. Sci. 2021, 22, 2681. [Google Scholar] [CrossRef]
- Buzhdygan, T.P.; DeOre, B.J.; Baldwin-Leclair, A.; Bullock, T.A.; McGary, H.M.; Khan, J.A.; Razmpour, R.; Hale, J.F.; Galie, P.A.; Potula, R.; et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol. Dis. 2020, 146, 105131. [Google Scholar] [CrossRef]
- DeOre, B.J.; Tran, K.A.; Andrews, A.M.; Ramirez, S.H.; Galie, P.A. SARS-CoV-2 Spike Protein Disrupts Blood-Brain Barrier Integrity via RhoA Activation. J. Neuroimmune Pharmacol. 2021, 16, 722–728. [Google Scholar] [CrossRef]
- Nation, D.A.; Sweeney, M.D.; Montagne, A.; Sagare, A.P.; D’Orazio, L.M.; Pachicano, M.; Sepehrband, F.; Nelson, A.R.; Buennagel, D.P.; Harrington, M.G.; et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 2019, 25, 270–276. [Google Scholar] [CrossRef]
- Zhang, L.; Zhou, L.; Bao, L.; Liu, J.; Zhu, H.; Lv, Q.; Liu, R.; Chen, W.; Tong, W.; Wei, Q.; et al. SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct. Target. Ther. 2021, 6, 337. [Google Scholar] [CrossRef]
- Krasemann, S.; Haferkamp, U.; Pfefferle, S.; Woo, M.S.; Heinrich, F.; Schweizer, M.; Appelt-Menzel, A.; Cubukova, A.; Barenberg, J.; Leu, J.; et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022, 17, 307–320. [Google Scholar] [CrossRef]
- Petrovszki, D.; Walter, F.R.; Vigh, J.P.; Kocsis, A.; Valkai, S.; Deli, M.A.; Der, A. Penetration of the SARS-CoV-2 Spike Protein across the Blood-Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing. Biomedicines 2022, 10, 188. [Google Scholar] [CrossRef]
- Wirth, K.J.; Scheibenbogen, C.; Paul, F. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J. Transl. Med. 2021, 19, 471. [Google Scholar] [CrossRef]
- Sun, Z.; Zhao, H.; Fang, D.; Davis, C.T.; Shi, D.S.; Lei, K.; Rich, B.E.; Winter, J.M.; Guo, L.; Sorensen, L.K.; et al. Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling. Neuron 2022, 110, 3106–3120.e3107. [Google Scholar] [CrossRef]
- Wierzba-Bobrowicz, T.; Krajewski, P.; Tarka, S.; Acewicz, A.; Felczak, P.; Stepien, T.; Golan, M.P.; Grzegorczyk, M. Neuropathological analysis of the brains of fifty-two patients with COVID-19. Folia Neuropathol. 2021, 59, 219–231. [Google Scholar] [CrossRef]
- Etter, M.M.; Martins, T.A.; Kulsvehagen, L.; Possnecker, E.; Duchemin, W.; Hogan, S.; Sanabria-Diaz, G.; Muller, J.; Chiappini, A.; Rychen, J.; et al. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: A prospective cross-sectional study. Nat. Commun. 2022, 13, 6777. [Google Scholar] [CrossRef]
- Chaumont, H.; Kaczorowski, F.; San-Galli, A.; Michel, P.P.; Tressieres, B.; Roze, E.; Quadrio, I.; Lannuzel, A. Cerebrospinal fluid biomarkers in SARS-CoV-2 patients with acute neurological syndromes. Rev. Neurol. 2022. [Google Scholar] [CrossRef]
- Ferreira de Araujo, J.L.; Menezes, D.; Saraiva-Duarte, J.M.; de Lima Ferreira, L.; Santana de Aguiar, R.; Pedra de Souza, R. Systematic review of host genetic association with COVID-19 prognosis and susceptibility: What have we learned in 2020? Rev. Med. Virol. 2022, 32, e2283. [Google Scholar] [CrossRef] [PubMed]
- Gkouskou, K.; Vasilogiannakopoulou, T.; Andreakos, E.; Davanos, N.; Gazouli, M.; Sanoudou, D.; Eliopoulos, A.G. COVID-19 enters the expanding network of apolipoprotein E4-related pathologies. Redox. Biol. 2021, 41, 101938. [Google Scholar] [CrossRef]
- Ortiz, G.G.; Velazquez-Brizuela, I.E.; Ortiz-Velazquez, G.E.; Ocampo-Alfaro, M.J.; Salazar-Flores, J.; Delgado-Lara, D.L.C.; Torres-Sanchez, E.D. Alzheimer’s Disease and SARS-CoV-2: Pathophysiological Analysis and Social Context. Brain Sci. 2022, 12, 1405. [Google Scholar] [CrossRef]
- Goldstein, M.R.; Poland, G.A.; Graeber, A.C.W. Does apolipoprotein E genotype predict COVID-19 severity? QJM 2020, 113, 529–530. [Google Scholar] [CrossRef] [PubMed]
- Gupta, K.; Kaur, G.; Pathak, T.; Banerjee, I. Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity. Gene 2022, 844, 146790. [Google Scholar] [CrossRef]
- Montagne, A.; Nation, D.A.; Sagare, A.P.; Barisano, G.; Sweeney, M.D.; Chakhoyan, A.; Pachicano, M.; Joe, E.; Nelson, A.R.; D’Orazio, L.M.; et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 2020, 581, 71–76. [Google Scholar] [CrossRef]
- Onofrio, L.; Caraglia, M.; Facchini, G.; Margherita, V.; Placido, S.; Buonerba, C. Toll-like receptors and COVID-19: A two-faced story with an exciting ending. Future Sci. OA 2020, 6, FSO605. [Google Scholar] [CrossRef]
- Sariol, A.; Perlman, S. SARS-CoV-2 takes its Toll. Nat. Immunol. 2021, 22, 801–802. [Google Scholar] [CrossRef]
- Singh, H.; Singh, A.; Khan, A.A.; Gupta, V. Immune mediating molecules and pathogenesis of COVID-19-associated neurological disease. Microb. Pathog. 2021, 158, 105023. [Google Scholar] [CrossRef] [PubMed]
- Khanmohammadi, S.; Rezaei, N. Role of Toll-like receptors in the pathogenesis of COVID-19. J. Med. Virol. 2021, 93, 2735–2739. [Google Scholar] [CrossRef] [PubMed]
- Jack, C.S.; Arbour, N.; Manusow, J.; Montgrain, V.; Blain, M.; McCrea, E.; Shapiro, A.; Antel, J.P. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 2005, 175, 4320–4330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vargas, G.; Medeiros Geraldo, L.H.; Gedeao Salomao, N.; Viana Paes, M.; Regina Souza Lima, F.; Carvalho Alcantara Gomes, F. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives. Brain Behav. Immun. Health 2020, 7, 100127. [Google Scholar] [CrossRef] [PubMed]
- Zheng, M.; Karki, R.; Williams, E.P.; Yang, D.; Fitzpatrick, E.; Vogel, P.; Jonsson, C.B.; Kanneganti, T.D. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat. Immunol. 2021, 22, 829–838. [Google Scholar] [CrossRef] [PubMed]
- Aboudounya, M.M.; Heads, R.J. COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation. Mediat. Inflamm. 2021, 2021, 8874339. [Google Scholar] [CrossRef]
- Manan, A.; Pirzada, R.H.; Haseeb, M.; Choi, S. Toll-like Receptor Mediation in SARS-CoV-2: A Therapeutic Approach. Int. J. Mol. Sci. 2022, 23, 10716. [Google Scholar] [CrossRef] [PubMed]
- Kaushik, D.; Bhandari, R.; Kuhad, A. TLR4 as a therapeutic target for respiratory and neurological complications of SARS-CoV-2. Expert Opin. Ther. Targets 2021, 25, 491–508. [Google Scholar] [CrossRef] [PubMed]
- Tsilioni, I.; Theoharides, T.C. Recombinant SARS-CoV-2 Spike Protein and its Receptor Binding Domain stimulate release of different pro-inflammatory mediators via activation of distinct receptors on human microglia cells. Res. Sq. 2023. [Google Scholar] [CrossRef]
- Dos Santos, S.E.; Medeiros, M.; Porfirio, J.; Tavares, W.; Pessoa, L.; Grinberg, L.; Leite, R.E.P.; Ferretti-Rebustini, R.E.L.; Suemoto, C.K.; Filho, W.J.; et al. Similar Microglial Cell Densities across Brain Structures and Mammalian Species: Implications for Brain Tissue Function. J. Neurosci. 2020, 40, 4622–4643. [Google Scholar] [CrossRef]
- Colonna, M.; Butovsky, O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017, 35, 441–468. [Google Scholar] [CrossRef]
- Perry, V.H.; Nicoll, J.A.; Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 2010, 6, 193–201. [Google Scholar] [CrossRef]
- Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science 2016, 353, 777–783. [Google Scholar] [CrossRef]
- Angelova, D.M.; Brown, D.R. Microglia and the aging brain: Are senescent microglia the key to neurodegeneration? J. Neurochem. 2019, 151, 676–688. [Google Scholar] [CrossRef] [Green Version]
- Bachiller, S.; Jimenez-Ferrer, I.; Paulus, A.; Yang, Y.; Swanberg, M.; Deierborg, T.; Boza-Serrano, A. Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Front. Cell. Neurosci. 2018, 12, 488. [Google Scholar] [CrossRef] [Green Version]
- Hickman, S.; Izzy, S.; Sen, P.; Morsett, L.; El, K.J. Microglia in neurodegeneration. Nat. Neurosci. 2018, 21, 1359–1369. [Google Scholar] [CrossRef]
- Liberman, A.C.; Trias, E.; da Silva, C.L.; Trindade, P.; Dos Santos, P.M.; Refojo, D.; Hedin-Pereira, C.; Serfaty, C.A. Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System. Neuroimmunomodulation 2018, 25, 246–270. [Google Scholar] [CrossRef] [Green Version]
- Xu, L.; He, D.; Bai, Y. Microglia-Mediated Inflammation and Neurodegenerative Disease. Mol. Neurobiol. 2016, 53, 6709–6715. [Google Scholar] [CrossRef]
- Subhramanyam, C.S.; Wang, C.; Hu, Q.; Dheen, S.T. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin. Cell Dev. Biol. 2019, 94, 112–120. [Google Scholar] [CrossRef]
- Voet, S.; Prinz, M.; van Loo, G. Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. Trends Mol. Med. 2019, 25, 112–123. [Google Scholar] [CrossRef]
- Goncalves de Andrade, E.; Simoncicova, E.; Carrier, M.; Vecchiarelli, H.A.; Robert, M.E.; Tremblay, M.E. Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic. Front. Cell. Neurosci. 2021, 15, 647378. [Google Scholar] [CrossRef]
- Schwabenland, M.; Salie, H.; Tanevski, J.; Killmer, S.; Lago, M.S.; Schlaak, A.E.; Mayer, L.; Matschke, J.; Puschel, K.; Fitzek, A.; et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 2021, 54, 1594–1610.e1511. [Google Scholar] [CrossRef]
- Poloni, T.E.; Medici, V.; Moretti, M.; Visona, S.D.; Cirrincione, A.; Carlos, A.F.; Davin, A.; Gagliardi, S.; Pansarasa, O.; Cereda, C.; et al. COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Brain Pathol. 2021, 31, e12997. [Google Scholar] [CrossRef]
- Poloni, T.E.; Moretti, M.; Medici, V.; Turturici, E.; Belli, G.; Cavriani, E.; Visona, S.D.; Rossi, M.; Fantini, V.; Ferrari, R.R.; et al. COVID-19 Pathology in the Lung, Kidney, Heart and Brain: The Different Roles of T-Cells, Macrophages, and Microthrombosis. Cells 2022, 11, 3124. [Google Scholar] [CrossRef] [PubMed]
- Rai, S.N.; Tiwari, N.; Singh, P.; Singh, A.K.; Mishra, D.; Imran, M.; Singh, S.; Hooshmandi, E.; Vamanu, E.; Singh, S.K.; et al. Exploring the Paradox of COVID-19 in Neurological Complications with Emphasis on Parkinson’s and Alzheimer’s Disease. Oxid. Med. Cell. Longev. 2022, 2022, 3012778. [Google Scholar] [CrossRef]
- Baazaoui, N.; Iqbal, K. COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences. J. Alzheimers Dis. 2022, 88, 399–416. [Google Scholar] [CrossRef]
- Fu, Y.W.; Xu, H.S.; Liu, S.J. COVID-19 and neurodegenerative diseases. Eur. Rev. Med. Pharmacol. Sci. 2022, 26, 4535–4544. [Google Scholar] [CrossRef] [PubMed]
- Steenblock, C.; Todorov, V.; Kanczkowski, W.; Eisenhofer, G.; Schedl, A.; Wong, M.L.; Licinio, J.; Bauer, M.; Young, A.H.; Gainetdinov, R.R.; et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol. Psychiatry 2020, 25, 1611–1617. [Google Scholar] [CrossRef]
- Theoharides, T.C. The impact of psychological stress on mast cells. Ann. Allergy Asthma Immunol. 2020, 125, 388–392. [Google Scholar] [CrossRef]
- Manchia, M.; Gathier, A.W.; Yapici-Eser, H.; Schmidt, M.V.; de Quervain, D.; van Amelsvoort, T.; Bisson, J.I.; Cryan, J.F.; Howes, O.D.; Pinto, L.; et al. The impact of the prolonged COVID-19 pandemic on stress resilience and mental health: A critical review across waves. Eur. Neuropsychopharmacol. 2022, 55, 22–83. [Google Scholar] [CrossRef]
- Lindert, J.; Jakubauskiene, M.; Bilsen, J. The COVID-19 disaster and mental health-assessing, responding and recovering. Eur. J. Public Health 2021, 31 (Suppl. 4), iv31–iv35. [Google Scholar] [CrossRef]
- Dijkstra, A.; Elbert, S.P. Detecting and Preventing Defensive Reactions Toward Persuasive Information on Fruit and Vegetable Consumption Using Induced Eye Movements. Front. Psychol. 2020, 11, 578287. [Google Scholar] [CrossRef]
- Patra, R.; Das, N.C.; Mukherjee, S. Toll-Like Receptors (TLRs) as Therapeutic Targets for Treating SARS-CoV-2: An Immunobiological Perspective. Adv. Exp. Med. Biol. 2021, 1352, 87–109. [Google Scholar] [CrossRef]
- Wallach, T.; Raden, M.; Hinkelmann, L.; Brehm, M.; Rabsch, D.; Weidling, H.; Kruger, C.; Kettenmann, H.; Backofen, R.; Lehnardt, S. Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia. Front. Immunol. 2022, 13, 1066456. [Google Scholar] [CrossRef] [PubMed]
- Martin, S.; Dicou, E.; Vincent, J.P.; Mazella, J. Neurotensin and the neurotensin receptor-3 in microglial cells. J. Neurosci. Res. 2005, 81, 322–326. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Ji, P.; Riopelle, R.J.; Dow, K.E. Functional expression of corticotropin-releasing hormone (CRH) receptor 1 in cultured rat microglia. J. Neurochem. 2002, 80, 287–294. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kempuraj, D.; Selvakumar, G.P.; Ahmed, M.E.; Raikwar, S.P.; Thangavel, R.; Khan, A.; Zaheer, S.A.; Iyer, S.S.; Burton, C.; James, D.; et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist 2020, 26, 402–414. [Google Scholar] [CrossRef]
- Patel, A.B.; Tsilioni, I.; Leeman, S.E.; Theoharides, T.C. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc. Natl. Acad. Sci. USA 2016, 113, E7049–E7058. [Google Scholar] [CrossRef] [Green Version]
- Niraula, A.; Sheridan, J.F.; Godbout, J.P. Microglia Priming with Aging and Stress. Neuropsychopharmacology 2016, 42, 318–333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carrier, M.; Simoncicova, E.; St-Pierre, M.K.; McKee, C.; Tremblay, M.E. Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk. Front. Mol. Neurosci. 2021, 14, 749737. [Google Scholar] [CrossRef] [PubMed]
- Rahimian, R.; Wakid, M.; O’Leary, L.A.; Mechawar, N. The emerging tale of microglia in psychiatric disorders. Neurosci. Biobehav. Rev. 2021, 131, 1–29. [Google Scholar] [CrossRef]
- Wohleb, E.S. Neuron-Microglia Interactions in Mental Health Disorders: “For Better, and For Worse”. Front. Immunol. 2016, 7, 544. [Google Scholar] [CrossRef] [Green Version]
- Troubat, R.; Barone, P.; Leman, S.; Desmidt, T.; Cressant, A.; Atanasova, B.; Brizard, B.; El Hage, W.; Surget, A.; Belzung, C.; et al. Neuroinflammation and depression: A review. Eur. J. Neurosci. 2021, 53, 151–171. [Google Scholar] [CrossRef]
- Brites, D.; Fernandes, A. Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front. Cell. Neurosci. 2015, 9, 476. [Google Scholar] [CrossRef] [Green Version]
- Steardo, L., Jr.; Steardo, L.; Verkhratsky, A. Psychiatric face of COVID-19. Transl. Psychiatry 2020, 10, 261. [Google Scholar] [CrossRef]
- Dixon, L.; Varley, J.; Gontsarova, A.; Mallon, D.; Tona, F.; Muir, D.; Luqmani, A.; Jenkins, I.H.; Nicholas, R.; Jones, B.; et al. COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia. Neurol. Neuroimmunol. Neuroinflamm. 2020, 7, e789. [Google Scholar] [CrossRef]
- Boroujeni, M.E.; Simani, L.; Bluyssen, H.A.R.; Samadikhah, H.R.; Zamanlui Benisi, S.; Hassani, S.; Akbari Dilmaghani, N.; Fathi, M.; Vakili, K.; Mahmoudiasl, G.R.; et al. Inflammatory Response Leads to Neuronal Death in Human Post-Mortem Cerebral Cortex in Patients with COVID-19. ACS Chem. Neurosci. 2021, 12, 2143–2150. [Google Scholar] [CrossRef]
- Shen, W.B.; Logue, J.; Yang, P.; Baracco, L.; Elahi, M.; Reece, E.A.; Wang, B.; Li, L.; Blanchard, T.G.; Han, Z.; et al. SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology. bioRxiv 2022. [Google Scholar] [CrossRef]
- Radhakrishnan, R.K.; Kandasamy, M. SARS-CoV-2-Mediated Neuropathogenesis, Deterioration of Hippocampal Neurogenesis and Dementia. Am. J. Alzheimers Dis. Other Demen. 2022, 37, 15333175221078418. [Google Scholar] [CrossRef]
- Welcome, M.O.; Mastorakis, N.E. Neuropathophysiology of coronavirus disease 2019: Neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection. Inflammopharmacology 2021, 29, 939–963. [Google Scholar] [CrossRef]
- Magro, C.M.; Mulvey, J.; Kubiak, J.; Mikhail, S.; Suster, D.; Crowson, A.N.; Laurence, J.; Nuovo, G. Severe COVID-19: A multifaceted viral vasculopathy syndrome. Ann. Diagn. Pathol. 2021, 50, 151645. [Google Scholar] [CrossRef]
- Harvey, W.T.; Carabelli, A.M.; Jackson, B.; Gupta, R.K.; Thomson, E.C.; Harrison, E.M.; Ludden, C.; Reeve, R.; Rambaut, A.; Consortium, C.-G.U.; et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 2021, 19, 409–424. [Google Scholar] [CrossRef]
- Hendriksen, E.; van Bergeijk, D.; Oosting, R.S.; Redegeld, F.A. Mast cells in neuroinflammation and brain disorders. Neurosci. Biobehav. Rev. 2017, 79, 119–133. [Google Scholar] [CrossRef]
- Skaper, S.D.; Facci, L.; Zusso, M.; Giusti, P. Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons. Neuroscientist 2017, 23, 478–498. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Wang, Y.; Dong, H.; Xu, Y.; Zhang, S. Induction of Microglial Activation by Mediators Released from Mast Cells. Cell. Physiol. Biochem. 2016, 38, 1520–1531. [Google Scholar] [CrossRef] [PubMed]
- Kempuraj, D.; Selvakumar, G.P.; Zaheer, S.; Thangavel, R.; Ahmed, M.E.; Raikwar, S.; Govindarajan, R.; Iyer, S.; Zaheer, A. Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease. J. Neuroimmune Pharmacol. 2018, 13, 100–112. [Google Scholar] [CrossRef] [Green Version]
- Dong, H.; Zhang, X.; Wang, Y.; Zhou, X.; Qian, Y.; Zhang, S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol. Neurobiol. 2017, 54, 997–1007. [Google Scholar] [CrossRef] [PubMed]
- Selvakumar, G.P.; Ahmed, M.E.; Thangavel, R.; Kempuraj, D.; Dubova, I.; Raikwar, S.P.; Zaheer, S.; Iyer, S.S.; Zaheer, A. A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice. Brain Behav. Immun. 2020, 87, 429–443. [Google Scholar] [CrossRef]
- Kempuraj, D.; Thangavel, R.; Selvakumar, G.P.; Ahmed, M.E.; Zaheer, S.; Raikwar, S.P.; Zahoor, H.; Saeed, D.; Dubova, I.; Giler, G.; et al. Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-kappaB. Mol. Neurobiol. 2019, 56, 1681–1693. [Google Scholar] [CrossRef]
- Dong, H.; Wang, Y.; Zhang, X.; Zhang, X.; Qian, Y.; Ding, H.; Zhang, S. Stabilization of Brain Mast Cells Alleviates LPS-Induced Neuroinflammation by Inhibiting Microglia Activation. Front. Cell. Neurosci. 2019, 13, 191. [Google Scholar] [CrossRef]
- Wang, Y.; Sha, H.; Zhou, L.; Chen, Y.; Zhou, Q.; Dong, H.; Qian, Y. The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus. Mediat. Inflamm. 2020, 2020, 8098439. [Google Scholar] [CrossRef]
- Zhang, X.; Dong, H.; Li, N.; Zhang, S.; Sun, J.; Zhang, S.; Qian, Y. Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis 1. J. Neuroinflamm. 2016, 13, 127. [Google Scholar] [CrossRef] [Green Version]
- Bugajski, A.J.; Chlap, Z.; Gadek-Michalska, A.; Borycz, J.; Bugajski, J. Degranulation and decrease in histamine levels of thalamic mast cells coincides with corticosterone secretion induced by compound 48/80. Inflamm. Res. 1995, 44 (Suppl. 1), S50–S51. [Google Scholar] [CrossRef]
- Kalogeromitros, D.; Syrigou, E.I.; Makris, M.; Kempuraj, D.; Stavrianeas, N.G.; Vasiadi, M.; Theoharides, T.C. Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis. Ann. Allergy Asthma Immunol. 2007, 98, 269–273. [Google Scholar] [CrossRef] [PubMed]
- Matsumoto, I.; Inoue, Y.; Shimada, T.; Aikawa, T. Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs. J. Exp. Med. 2001, 194, 71–78. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Donelan, J.M.; Papadopoulou, N.; Cao, J.; Kempuraj, D.; Conti, P. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol. Sci. 2004, 25, 563–568. [Google Scholar] [CrossRef]
- Scaccianoce, S.; Lombardo, K.; Nicolai, R.; Affricano, D.; Angelucci, L. Studies on the involvement of histamine in the hypothalamic-pituitary-adrenal axis activation induced by nerve growth factor. Life Sci. 2000, 67, 3143–3152. [Google Scholar] [CrossRef]
- Mastorakos, G.; Chrousos, G.P.; Weber, J.S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J. Clin. Endocrinol. Metab. 1993, 77, 1690–1694. [Google Scholar]
- Kempuraj, D.; Papadopoulou, N.G.; Lytinas, M.; Huang, M.; Kandere-Grzybowska, K.; Madhappan, B.; Boucher, W.; Christodoulou, S.; Athanassiou, A.; Theoharides, T.C. Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology 2004, 145, 43–48. [Google Scholar] [CrossRef] [Green Version]
- Milligan, A.A.; Porter, T.; Quek, H.; White, A.; Haynes, J.; Jackaman, C.; Villemagne, V.; Munyard, K.; Laws, S.M.; Verdile, G.; et al. Chronic stress and Alzheimer’s disease: The interplay between the hypothalamic-pituitary-adrenal axis, genetics and microglia. Biol. Rev. Camb. Philos. Soc. 2021, 96, 2209–2228. [Google Scholar] [CrossRef]
- Alysandratos, K.D.; Asadi, S.; Angelidou, A.; Zhang, B.; Sismanopoulos, N.; Yang, H.; Critchfield, A.; Theoharides, T.C. Neurotensin and CRH interactions augment human mast cell activation. PLoS ONE 2012, 7, e48934. [Google Scholar] [CrossRef] [Green Version]
- Kempuraj, D.; Mentor, S.; Thangavel, R.; Ahmed, M.E.; Selvakumar, G.P.; Raikwar, S.P.; Dubova, I.; Zaheer, S.; Iyer, S.S.; Zaheer, A. Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease. Front. Cell. Neurosci. 2019, 13, 54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, W.; Zhang, X.; Zhang, Y.; Qu, C.; Zhou, X.; Zhang, S. Histamine Induces Microglia Activation and the Release of Proinflammatory Mediators in Rat Brain Via H1R or H4R. J. Neuroimmune Pharmacol. 2020, 15, 280–291. [Google Scholar] [CrossRef]
- Zhang, S.; Zeng, X.; Yang, H.; Hu, G.; He, S. Mast cell tryptase induces microglia activation via protease-activated receptor 2 signaling. Cell. Physiol. Biochem. 2012, 29, 931–940. [Google Scholar] [CrossRef] [PubMed]
- Zhou, L.; Chen, L.; Li, X.; Li, T.; Dong, Z.; Wang, Y.T. Food allergy induces alteration in brain inflammatory status and cognitive impairments. Behav. Brain Res. 2019, 364, 374–382. [Google Scholar] [CrossRef]
- McClain, J.L.; Mazzotta, E.A.; Maradiaga, N.; Duque-Wilckens, N.; Grants, I.; Robison, A.J.; Christofi, F.L.; Moeser, A.J.; Gulbransen, B.D. Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 319, G655–G668. [Google Scholar] [CrossRef] [PubMed]
- Galli, S.J.; Tsai, M.; Piliponsky, A.M. The development of allergic inflammation. Nature 2008, 454, 445–454. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Alysandratos, K.D.; Angelidou, A.; Delivanis, D.A.; Sismanopoulos, N.; Zhang, B.; Asadi, S.; Vasiadi, M.; Weng, Z.; Miniati, A.; et al. Mast cells and inflammation. Biochim. Biophys. Acta 2012, 1822, 21–33. [Google Scholar] [CrossRef] [Green Version]
- Mukai, K.; Tsai, M.; Saito, H.; Galli, S.J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 2018, 282, 121–150. [Google Scholar] [CrossRef]
- Gurish, M.F.; Austen, K.F. Developmental origin and functional specialization of mast cell subsets 1. Immunity 2012, 37, 25–33. [Google Scholar] [CrossRef] [Green Version]
- Olivera, A.; Beaven, M.A.; Metcalfe, D.D. Mast cells signal their importance in health and disease. J. Allergy Clin. Immunol. 2018, 142, 381–393. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Valent, P.; Akin, C. Mast Cells, Mastocytosis, and Related Disorders. N. Engl. J. Med. 2015, 373, 163–172. [Google Scholar] [CrossRef]
- Falduto, G.H.; Pfeiffer, A.; Luker, A.; Metcalfe, D.D.; Olivera, A. Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications. Pharmacol. Ther. 2021, 220, 107718. [Google Scholar] [CrossRef] [PubMed]
- Levi-Schaffer, F.; Gibbs, B.F.; Hallgren, J.; Pucillo, C.; Redegeld, F.; Siebenhaar, F.; Vitte, J.; Mezouar, S.; Michel, M.; Puzzovio, P.G.; et al. Selected recent advances in understanding the role of human mast cells in health and disease. J. Allergy Clin. Immunol. 2022, 149, 1833–1844. [Google Scholar] [CrossRef]
- Kolkhir, P.; Elieh-Ali-Komi, D.; Metz, M.; Siebenhaar, F.; Maurer, M. Understanding human mast cells: Lesson from therapies for allergic and non-allergic diseases. Nat. Rev. Immunol. 2022, 22, 294–308. [Google Scholar] [CrossRef] [PubMed]
- Dahlin, J.S.; Maurer, M.; Metcalfe, D.D.; Pejler, G.; Sagi-Eisenberg, R.; Nilsson, G. The ingenious mast cell: Contemporary insights into mast cell behavior and function. Allergy 2022, 77, 83–99. [Google Scholar] [CrossRef]
- Bawazeer, M.A.; Theoharides, T.C. IL-33 stimulates human mast cell release of CCL5 and CCL2 via MAPK and NF-kappaB, inhibited by methoxyluteolin. Eur. J. Pharmacol. 2019, 865, 172760. [Google Scholar] [CrossRef]
- Kandere-Grzybowska, K.; Letourneau, R.; Kempuraj, D.; Donelan, J.; Poplawski, S.; Boucher, W.; Athanassiou, A.; Theoharides, T.C. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J. Immunol. 2003, 171, 4830–4836. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taracanova, A.; Alevizos, M.; Karagkouni, A.; Weng, Z.; Norwitz, E.; Conti, P.; Leeman, S.E.; Theoharides, T.C. SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors. Proc. Natl. Acad. Sci. USA 2017, 114, E4002–E4009. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Petra, A.I.; Taracanova, A.; Panagiotidou, S.; Conti, P. Targeting IL-33 in autoimmunity and inflammation. J. Pharmacol. Exp. Ther. 2015, 354, 24–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liew, F.Y.; Pitman, N.I.; McInnes, I.B. Disease-associated functions of IL-33: The new kid in the IL-1 family. Nat. Rev. Immunol. 2010, 10, 103–110. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Leeman, S.E. Effect of IL-33 on de novo synthesized mediators from human mast cells. J. Allergy Clin. Immunol. 2019, 143, 451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saluja, R.; Khan, M.; Church, M.K.; Maurer, M. The role of IL-33 and mast cells in allergy and inflammation. Clin. Transl. Allergy 2015, 5, 33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, B.; Asadi, S.; Weng, Z.; Sismanopoulos, N.; Theoharides, T.C. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PLoS ONE 2012, 7, e49767. [Google Scholar] [CrossRef]
- Collins, L.V.; Hajizadeh, S.; Holme, E.; Jonsson, I.M.; Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 2004, 75, 995–1000. [Google Scholar] [CrossRef] [PubMed]
- Sun, S.; Sursal, T.; Adibnia, Y.; Zhao, C.; Zheng, Y.; Li, H.; Otterbein, L.E.; Hauser, C.J.; Itagaki, K. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS ONE 2013, 8, e59989. [Google Scholar] [CrossRef] [Green Version]
- Traina, G. Mast cells in the brain—Old cells, new target. J. Integr. Neurosci. 2017, 16, S69–S83. [Google Scholar] [CrossRef]
- Rozniecki, J.J.; Dimitriadou, V.; Lambracht-Hall, M.; Pang, X.; Theoharides, T.C. Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res. 1999, 849, 1–15. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Konstantinidou, A.D. Corticotropin-releasing hormone and the blood-brain-barrier. Front. Biosci. 2007, 12, 1615–1628. [Google Scholar] [CrossRef] [Green Version]
- Dimitriadou, V.; Rouleau, A.; Trung Tuong, M.D.; Newlands, G.J.; Miller, H.R.; Luffau, G.; Schwartz, J.C.; Garbarg, M. Functional relationships between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. Neuroscience 1997, 77, 829–839. [Google Scholar] [CrossRef]
- Torrealba, F.; Riveros, M.E.; Contreras, M.; Valdes, J.L. Histamine and motivation. Front. Syst. Neurosci. 2012, 6, 51. [Google Scholar] [CrossRef] [Green Version]
- Nomura, H.; Shimizume, R.; Ikegaya, Y. Histamine: A Key Neuromodulator of Memory Consolidation and Retrieval. Curr. Top. Behav. Neurosci. 2021, 59, 329–353. [Google Scholar] [CrossRef]
- Moura, D.S.; Sultan, S.; Georgin-Lavialle, S.; Barete, S.; Lortholary, O.; Gaillard, R.; Hermine, O. Evidence for cognitive impairment in mastocytosis: Prevalence, features and correlations to depression. PLoS ONE 2012, 7, e39468. [Google Scholar] [CrossRef]
- Spolak-Bobryk, N.; Romantowski, J.; Kujawska-Danecka, H.; Niedoszytko, M. Mastocytosis patients’ cognitive dysfunctions correlate with the presence of spindle-shaped mast cells in bone marrow. Clin. Transl. Allergy 2022, 12, e12093. [Google Scholar] [CrossRef]
- Boddaert, N.; Salvador, A.; Chandesris, M.O.; Lemaitre, H.; Grevent, D.; Gauthier, C.; Naggara, O.; Georgin-Lavialle, S.; Moura, D.S.; Munsch, F.; et al. Neuroimaging evidence of brain abnormalities in mastocytosis. Transl. Psychiatry 2017, 7, e1197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spath-Schwalbe, E.; Born, J.; Schrezenmeier, H.; Bornstein, S.R.; Stromeyer, P.; Drechsler, S.; Fehm, H.L.; Porzsolt, F. Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man. J. Clin. Endocrinol. Metab. 1994, 79, 1212–1214. [Google Scholar] [CrossRef] [PubMed]
- Theoharides, T.C. Effect of Stress on Neuroimmune Processes. Clin. Ther. 2020, 42, 1007–1014. [Google Scholar] [CrossRef] [PubMed]
- Esposito, P.; Chandler, N.; Kandere, K.; Basu, S.; Jacobson, S.; Connolly, R.; Tutor, D.; Theoharides, T.C. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J. Pharmacol. Exp. Ther. 2002, 303, 1061–1066. [Google Scholar] [CrossRef]
- Fiorentino, M.; Sapone, A.; Senger, S.; Camhi, S.S.; Kadzielski, S.M.; Buie, T.M.; Kelly, D.L.; Cascella, N.; Fasano, A. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol. Autism 2016, 7, 49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rozniecki, J.J.; Sahagian, G.G.; Kempuraj, D.; Tao, K.; Jocobson, S.; Zhang, B.; Theoharides, T.C. Brain metastases of mouse mammary adenocarcinoma is increased by acute stress. Brain Res. 2010, 1366, 204–210. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Rozniecki, J.J.; Sahagian, G.; Jocobson, S.; Kempuraj, D.; Conti, P.; Kalogeromitros, D. Impact of stress and mast cells on brain metastases. J. Neuroimmunol. 2008, 205, 1–7. [Google Scholar] [CrossRef]
- Abbott, N.J. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol. Neurobiol. 2000, 20, 131–147. [Google Scholar] [CrossRef]
- Pan, W.; Stone, K.P.; Hsuchou, H.; Manda, V.K.; Zhang, Y.; Kastin, A.J. Cytokine signaling modulates blood-brain barrier function. Curr. Pharm. Des. 2011, 17, 3729–3740. [Google Scholar] [CrossRef] [Green Version]
- Sayed, B.A.; Christy, A.L.; Walker, M.E.; Brown, M.A. Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: A role for neutrophil recruitment? J. Immunol. 2010, 184, 6891–6900. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Skaper, S.D. Impact of Inflammation on the Blood-Neural Barrier and Blood-Nerve Interface: From Review to Therapeutic Preview. Int. Rev. Neurobiol. 2017, 137, 29–45. [Google Scholar] [CrossRef]
- Sibilano, R.; Frossi, B.; Pucillo, C.E. Mast cell activation: A complex interplay of positive and negative signaling pathways. Eur. J. Immunol. 2014, 44, 2558–2566. [Google Scholar] [CrossRef]
- Xu, H.; Bin, N.R.; Sugita, S. Diverse exocytic pathways for mast cell mediators. Biochem. Soc. Trans. 2018, 46, 235–247. [Google Scholar] [CrossRef] [PubMed]
- Gilfillan, A.M.; Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol 2006, 6, 218–230. [Google Scholar] [CrossRef]
- Gaudenzio, N.; Sibilano, R.; Marichal, T.; Starkl, P.; Reber, L.L.; Cenac, N.; McNeil, B.D.; Dong, X.; Hernandez, J.D.; Sagi-Eisenberg, R.; et al. Different activation signals induce distinct mast cell degranulation strategies. J. Clin. Investig. 2016, 126, 3981–3998. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C. Neuroendocrinology of mast cells: Challenges and controversies. Exp. Dermatol. 2017, 26, 751–759. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Tsilioni, I.; Bawazeer, M. Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front. Cell. Neurosci. 2019, 13, 353. [Google Scholar] [CrossRef]
- Xu, H.; Shi, X.; Li, X.; Zou, J.; Zhou, C.; Liu, W.; Shao, H.; Chen, H.; Shi, L. Neurotransmitter and neuropeptide regulation of mast cell function: A systematic review. J. Neuroinflamm. 2020, 17, 356. [Google Scholar] [CrossRef]
- Sumpter, T.L.; Ho, C.H.; Pleet, A.R.; Tkacheva, O.A.; Shufesky, W.J.; Rojas-Canales, D.M.; Morelli, A.E.; Larregina, A.T. Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses. J. Allergy Clin. Immunol. 2015, 135, 1019–1030. [Google Scholar] [CrossRef] [Green Version]
- Levi-Montalcini, R.; Skaper, S.D.; Dal Toso, R.; Petrelli, L.; Leon, A. Nerve growth factor: From neurotrophin to neurokine. Trends Neurosci. 1996, 19, 514–520. [Google Scholar] [CrossRef]
- Donelan, J.; Boucher, W.; Papadopoulou, N.; Lytinas, M.; Papaliodis, D.; Dobner, P.; Theoharides, T.C. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc. Natl. Acad. Sci. USA 2006, 103, 7759–7764. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Zhang, B.; Kempuraj, D.; Tagen, M.; Vasiadi, M.; Angelidou, A.; Alysandratos, K.D.; Kalogeromitros, D.; Asadi, S.; Stavrianeas, N.; et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc. Natl. Acad. Sci. USA 2010, 107, 4448–4453. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Betchaku, T.; Douglas, W.W. Somatostatin-induced histamine secretion in mast cells. Characterization of the effect. Eur. J. Pharmacol. 1981, 69, 127–137. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Douglas, W.W. Mast cell histamine secretion in response to somatostatin analogues: Structural considerations. Eur. J. Pharmacol. 1981, 73, 131–136. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Papaliodis, D.; Tagen, M.; Konstantinidou, A.; Kempuraj, D.; Clemons, A. Chronic fatigue syndrome, mast cells, and tricyclic antidepressants. J. Clin. Psychopharmacol. 2005, 25, 515–520. [Google Scholar] [CrossRef]
- Gordon, J.R.; Galli, S.J. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature 1990, 346, 274–276. [Google Scholar] [CrossRef]
- Zhang, B.; Alysandratos, K.D.; Angelidou, A.; Asadi, S.; Sismanopoulos, N.; Delivanis, D.A.; Weng, Z.; Miniati, A.; Vasiadi, M.; Katsarou-Katsari, A.; et al. Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis. J. Allergy Clin. Immunol. 2011, 127, 1522–1531.e1528. [Google Scholar] [CrossRef] [Green Version]
- Taracanova, A.; Tsilioni, I.; Conti, P.; Norwitz, E.R.; Leeman, S.E.; Theoharides, T.C. Substance P and IL-33 administered together stimulate a marked secretion of IL-1beta from human mast cells, inhibited by methoxyluteolin. Proc. Natl. Acad. Sci. USA 2018, 115, E9381–E9390. [Google Scholar] [CrossRef] [Green Version]
- Yu, Y.; Blokhuis, B.R.; Garssen, J.; Redegeld, F.A. Non-IgE mediated mast cell activation. Eur. J. Pharmacol. 2016, 778, 33–43. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Kempuraj, D.; Tagen, M.; Conti, P.; Kalogeromitros, D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 2007, 217, 65–78. [Google Scholar] [CrossRef]
- Gagari, E.; Tsai, M.; Lantz, C.S.; Fox, L.G.; Galli, S.J. Differential release of mast cell interleukin-6 via c-kit. Blood 1997, 89, 2654–2663. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Boucher, W.; Spear, K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int. Arch. Allergy Immunol. 2002, 128, 344–350. [Google Scholar] [CrossRef]
- Brockow, K.; Akin, C.; Huber, M.; Metcalfe, D.D. IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis. Clin. Immunol. 2005, 115, 216–223. [Google Scholar] [CrossRef] [PubMed]
- Mayado, A.; Teodosio, C.; Garcia-Montero, A.C.; Matito, A.; Rodriguez-Caballero, A.; Morgado, J.M.; Muniz, C.; Jara-Acevedo, M.; Alvarez-Twose, I.; Sanchez-Munoz, L.; et al. Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression. Leukemia 2016, 30, 124–130. [Google Scholar] [CrossRef] [PubMed]
- Kaur, D.; Gomez, E.; Doe, C.; Berair, R.; Woodman, L.; Saunders, R.; Hollins, F.; Rose, F.R.; Amrani, Y.; May, R.; et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: Airway smooth muscle crosstalk. Allergy 2015, 70, 556–567. [Google Scholar] [CrossRef] [Green Version]
- Abraham, S.N.; St John, A.L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 2010, 10, 440–452. [Google Scholar] [CrossRef] [Green Version]
- Song, S.T.; Wu, M.L.; Zhang, H.J.; Su, X.; Wang, J.H. Mast Cell Activation Triggered by Retrovirus Promotes Acute Viral Infection. Front. Microbiol. 2022, 13, 798660. [Google Scholar] [CrossRef] [PubMed]
- Gebremeskel, S.; Schanin, J.; Coyle, K.M.; Butuci, M.; Luu, T.; Brock, E.C.; Xu, A.; Wong, A.; Leung, J.; Korver, W.; et al. Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody. Front. Immunol. 2021, 12, 650331. [Google Scholar] [CrossRef]
- Motta Junior, J.D.S.; Miggiolaro, A.; Nagashima, S.; de Paula, C.B.V.; Baena, C.P.; Scharfstein, J.; de Noronha, L. Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front. Immunol. 2020, 11, 574862. [Google Scholar] [CrossRef]
- Wu, M.L.; Liu, F.L.; Sun, J.; Li, X.; He, X.Y.; Zheng, H.Y.; Zhou, Y.H.; Yan, Q.; Chen, L.; Yu, G.Y.; et al. SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury. Signal Transduct. Target. Ther. 2021, 6, 428. [Google Scholar] [CrossRef]
- Tan, J.; Anderson, D.E.; Rathore, A.P.S.; O’Neill, A.; Mantri, C.K.; Saron, W.A.A.; Lee, C.; Cui, C.W.; Kang, A.E.Z.; Foo, R.; et al. Signatures of mast cell activation are associated with severe COVID-19. medRxiv 2021. [Google Scholar] [CrossRef]
- Zelechowska, P.; Brzezinska-Blaszczyk, E.; Agier, J.; Kozlowska, E. Different effectiveness of fungal pathogen-associated molecular patterns (PAMPs) in activating rat peritoneal mast cells. Immunol. Lett. 2022, 248, 7–15. [Google Scholar] [CrossRef]
- Krysko, O.; Bourne, J.H.; Kondakova, E.; Galova, E.A.; Whitworth, K.; Newby, M.L.; Bachert, C.; Hill, H.; Crispin, M.; Stamataki, Z.; et al. Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation. Front. Immunol. 2022, 13, 968981. [Google Scholar] [CrossRef]
- Takagi, D.; Ishiyama, K.; Suganami, M.; Ushijima, T.; Fujii, T.; Tazoe, Y.; Kawasaki, M.; Noguchi, K.; Makino, A. Manganese toxicity disrupts indole acetic acid homeostasis and suppresses the CO(2) assimilation reaction in rice leaves. Sci. Rep. 2021, 11, 20922. [Google Scholar] [CrossRef]
- Wechsler, J.B.; Butuci, M.; Wong, A.; Kamboj, A.P.; Youngblood, B.A. Mast cell activation is associated with post-acute COVID-19 syndrome. Allergy 2022, 77, 1288–1291. [Google Scholar] [CrossRef]
- da Silveira Gorman, R.; Syed, I.U. Connecting the Dots in Emerging Mast Cell Research: Do Factors Affecting Mast Cell Activation Provide a Missing Link between Adverse COVID-19 Outcomes and the Social Determinants of Health? Med. Sci. 2022, 10, 29. [Google Scholar] [CrossRef]
- Scozzi, D.; Cano, M.; Ma, L.; Zhou, D.; Zhu, J.H.; O’Halloran, J.A.; Goss, C.; Rauseo, A.M.; Liu, Z.; Sahu, S.K.; et al. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight 2021, 6, e143299. [Google Scholar] [CrossRef]
- Keykavousi, K.; Nourbakhsh, F.; Abdollahpour, N.; Fazeli, F.; Sedaghat, A.; Soheili, V.; Sahebkar, A. A Review of Routine Laboratory Biomarkers for the Detection of Severe COVID-19 Disease. Int. J. Anal. Chem. 2022, 2022, 9006487. [Google Scholar] [CrossRef] [PubMed]
- DeKosky, S.T.; Kochanek, P.M.; Valadka, A.B.; Clark, R.S.B.; Chou, S.H.; Au, A.K.; Horvat, C.; Jha, R.M.; Mannix, R.; Wisniewski, S.R.; et al. Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients. J. Neurotrauma 2021, 38, 1–43. [Google Scholar] [CrossRef]
- Frontera, J.A.; Boutajangout, A.; Masurkar, A.V.; Betensky, R.A.; Ge, Y.; Vedvyas, A.; Debure, L.; Moreira, A.; Lewis, A.; Huang, J.; et al. Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia. Alzheimers Dement. 2022, 18, 899–910. [Google Scholar] [CrossRef]
- Wang, Z.; Waldman, M.F.; Basavanhally, T.J.; Jacobs, A.R.; Lopez, G.; Perichon, R.Y.; Ma, J.J.; Mackenzie, E.M.; Healy, J.B.; Wang, Y.; et al. Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome. J. Transl. Med. 2022, 20, 486. [Google Scholar] [CrossRef] [PubMed]
- Kandikattu, H.K.; Venkateshaiah, S.U.; Kumar, S.; Mishra, A. IL-15 immunotherapy is a viable strategy for COVID-19. Cytokine Growth Factor Rev. 2020, 54, 24–31. [Google Scholar] [CrossRef]
- Lu, T.; Ma, R.; Dong, W.; Teng, K.Y.; Kollath, D.S.; Li, Z.; Yi, J.; Bustillos, C.; Ma, S.; Tian, L.; et al. Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19. Nat. Commun. 2022, 13, 2576. [Google Scholar] [CrossRef]
- Kassianidis, G.; Siampanos, A.; Poulakou, G.; Adamis, G.; Rapti, A.; Milionis, H.; Dalekos, G.N.; Petrakis, V.; Sympardi, S.; Metallidis, S.; et al. Calprotectin and Imbalances between Acute-Phase Mediators Are Associated with Critical Illness in COVID-19. Int. J. Mol. Sci. 2022, 23, 4894. [Google Scholar] [CrossRef] [PubMed]
- Yasuda, K.; Nakanishi, K.; Tsutsui, H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019, 20, 649. [Google Scholar] [CrossRef] [Green Version]
- Ihim, S.A.; Abubakar, S.D.; Zian, Z.; Sasaki, T.; Saffarioun, M.; Maleknia, S.; Azizi, G. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front. Immunol. 2022, 13, 919973. [Google Scholar] [CrossRef] [PubMed]
- Wu, M.; Xu, L.; Wang, Y.; Zhou, N.; Zhen, F.; Zhang, Y.; Qu, X.; Fan, H.; Liu, S.; Chen, Y.; et al. S100A8/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-kappaB signaling pathway. Brain Res. Bull. 2018, 143, 234–245. [Google Scholar] [CrossRef]
- Berg-Hansen, P.; Vandvik, B.; Fagerhol, M.; Holmoy, T. Calprotectin levels in the cerebrospinal fluid reflect disease activity in multiple sclerosis. J. Neuroimmunol. 2009, 216, 98–102. [Google Scholar] [CrossRef] [PubMed]
- Stascheit, F.; Hotter, B.; Klose, S.; Meisel, C.; Meisel, A.; Klehmet, J. Calprotectin in Chronic Inflammatory Demyelinating Polyneuropathy and Variants-A Potential Novel Biomarker of Disease Activity. Front. Neurol. 2021, 12, 723009. [Google Scholar] [CrossRef]
- Sudhof, T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 2008, 455, 903–911. [Google Scholar] [CrossRef] [Green Version]
- Camporesi, E.; Lashley, T.; Gobom, J.; Lantero-Rodriguez, J.; Hansson, O.; Zetterberg, H.; Blennow, K.; Becker, B. Neuroligin-1 in brain and CSF of neurodegenerative disorders: Investigation for synaptic biomarkers. Acta Neuropathol. Commun. 2021, 9, 19. [Google Scholar] [CrossRef]
- Dufort-Gervais, J.; Provost, C.; Charbonneau, L.; Norris, C.M.; Calon, F.; Mongrain, V.; Brouillette, J. Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers. Sci. Rep. 2020, 10, 6956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, K.; Gao, X.; Qi, H.; Li, J.; Zheng, Z.; Zhang, F. Gender differences in cognitive ability associated with genetic variants of NLGN4. Neuropsychobiology 2010, 62, 221–228. [Google Scholar] [CrossRef]
- Cantuti-Castelvetri, L.; Ojha, R.; Pedro, L.D.; Djannatian, M.; Franz, J.; Kuivanen, S.; van der Meer, F.; Kallio, K.; Kaya, T.; Anastasina, M.; et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020, 370, 856–860. [Google Scholar] [CrossRef] [PubMed]
- Aceti, A.; Margarucci, L.M.; Scaramucci, E.; Orsini, M.; Salerno, G.; Di Sante, G.; Gianfranceschi, G.; Di Liddo, R.; Valeriani, F.; Ria, F.; et al. Serum S100B protein as a marker of severity in COVID-19 patients. Sci. Rep. 2020, 10, 18665. [Google Scholar] [CrossRef]
- Zhou, S.; Zhu, W.; Zhang, Y.; Pan, S.; Bao, J. S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia. Inflamm. Res. 2018, 67, 937–949. [Google Scholar] [CrossRef]
- Xu, J.; Wang, H.; Won, S.J.; Basu, J.; Kapfhamer, D.; Swanson, R.A. Microglial activation induced by the alarmin S100B is regulated by poly(ADP-ribose) polymerase-1. Glia 2016, 64, 1869–1878. [Google Scholar] [CrossRef] [Green Version]
- Bianchi, R.; Kastrisianaki, E.; Giambanco, I.; Donato, R. S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J. Biol. Chem. 2011, 286, 7214–7226. [Google Scholar] [CrossRef] [Green Version]
- Hopman, J.H.; Santing, J.A.L.; Foks, K.A.; Verheul, R.J.; van der Linden, C.M.; van den Brand, C.L.; Jellema, K. Biomarker S100B in plasma a screening tool for mild traumatic brain injury in an emergency department. Brain Inj 2023, 37, 47–53. [Google Scholar] [CrossRef] [PubMed]
- Shahim, P.; Politis, A.; van der Merwe, A.; Moore, B.; Chou, Y.Y.; Pham, D.L.; Butman, J.A.; Diaz-Arrastia, R.; Gill, J.M.; Brody, D.L.; et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology 2020, 95, e610–e622. [Google Scholar] [CrossRef]
- Savarraj, J.; Park, E.S.; Colpo, G.D.; Hinds, S.N.; Morales, D.; Ahnstedt, H.; Paz, A.S.; Assing, A.; Liu, F.; Juneja, S.; et al. Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19. J. Neuroinflamm. 2021, 18, 277. [Google Scholar] [CrossRef]
- Park, D.; Joo, S.S.; Lee, H.J.; Choi, K.C.; Kim, S.U.; Kim, Y.B. Microtubule-associated protein 2, an early blood marker of ischemic brain injury. J. Neurosci. Res. 2012, 90, 461–467. [Google Scholar] [CrossRef]
- Hicks, C.; Dhiman, A.; Barrymore, C.; Goswami, T. Traumatic Brain Injury Biomarkers, Simulations and Kinetics. Bioengineering 2022, 9, 612. [Google Scholar] [CrossRef] [PubMed]
- Iaffaldano, P.; Ruggieri, M.; Viterbo, R.G.; Mastrapasqua, M.; Trojano, M. The improvement of cognitive functions is associated with a decrease of plasma Osteopontin levels in Natalizumab treated relapsing multiple sclerosis. Brain Behav. Immun. 2014, 35, 176–181. [Google Scholar] [CrossRef]
- Chai, Y.L.; Chong, J.R.; Raquib, A.R.; Xu, X.; Hilal, S.; Venketasubramanian, N.; Tan, B.Y.; Kumar, A.P.; Sethi, G.; Chen, C.P.; et al. Plasma osteopontin as a biomarker of Alzheimer’s disease and vascular cognitive impairment. Sci. Rep. 2021, 11, 4010. [Google Scholar] [CrossRef]
- Khalifa, S.; Holmstead, R.L.; Casida, J.E. Toxaphene degradation by iron(II) protoporphyrin systems. J. Agric. Food Chem. 1976, 24, 277–282. [Google Scholar] [CrossRef] [PubMed]
- Fernandez-Castaneda, A.; Lu, P.; Geraghty, A.C.; Song, E.; Lee, M.H.; Wood, J.; O’Dea, M.R.; Dutton, S.; Shamardani, K.; Nwangwu, K.; et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 2022, 185, 2452–2468.e2416. [Google Scholar] [CrossRef]
- Nazarinia, D.; Behzadifard, M.; Gholampour, J.; Karimi, R.; Gholampour, M. Eotaxin-1 (CCL11) in neuroinflammatory disorders and possible role in COVID-19 neurologic complications. Acta Neurol. Belg. 2022, 122, 865–869. [Google Scholar] [CrossRef] [PubMed]
- Spitzer, D.; Guerit, S.; Puetz, T.; Khel, M.I.; Armbrust, M.; Dunst, M.; Macas, J.; Zinke, J.; Devraj, G.; Jia, X.; et al. Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke. Acta Neuropathol. 2022, 144, 305–337. [Google Scholar] [CrossRef] [PubMed]
- Yan, Y.; Chen, R.; Wang, X.; Hu, K.; Huang, L.; Lu, M.; Hu, Q. CCL19 and CCR7 Expression, Signaling Pathways, and Adjuvant Functions in Viral Infection and Prevention. Front. Cell. Dev. Biol. 2019, 7, 212. [Google Scholar] [CrossRef] [Green Version]
- Tveita, A.; Murphy, S.L.; Holter, J.C.; Kildal, A.B.; Michelsen, A.E.; Lerum, T.V.; Kaarbo, M.; Heggelund, L.; Holten, A.R.; Finbraten, A.K.; et al. High circulating levels of the homeostatic chemokines CCL19 and CCL21 predict mortality and disease severity in COVID-19. J. Infect. Dis. 2022, 226, 2150–2160. [Google Scholar] [CrossRef] [PubMed]
- Kushner, P.; McCarberg, B.H.; Grange, L.; Kolosov, A.; Haveric, A.L.; Zucal, V.; Petruschke, R.; Bissonnette, S. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. NPJ Prim. Care Respir. Med. 2022, 32, 35. [Google Scholar] [CrossRef]
- Bicker, J.; Alves, G.; Fonseca, C.; Falcao, A.; Fortuna, A. Repairing blood-CNS barriers: Future therapeutic approaches for neuropsychiatric disorders. Pharmacol. Res. 2020, 162, 105226. [Google Scholar] [CrossRef]
- Alegre-Del-Rey, E.J.; Fenix-Caballero, S.; Salmeron-Navas, F.J.; Gil-Sierra, M.D.; Sierra-Sanchez, J.F.; Diaz-Alersi Rosety, R.L. Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19. Farm. Hosp. 2022, 46, 166–172. [Google Scholar]
- Dimopoulos, G.; de Mast, Q.; Markou, N.; Theodorakopoulou, M.; Komnos, A.; Mouktaroudi, M.; Netea, M.G.; Spyridopoulos, T.; Verheggen, R.J.; Hoogerwerf, J.; et al. Favorable Anakinra Responses in Severe COVID-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis. Cell Host Microbe 2020, 28, 117–123.e111. [Google Scholar] [CrossRef]
- Liu, J.; Dong, J.; Yu, Y.; Yang, X.; Shu, J.; Bao, H. Corticosteroids showed more efficacy in treating hospitalized patients with COVID-19 than standard care but the effect is minimal: A systematic review and meta-analysis. Front. Public Health 2022, 10, 847695. [Google Scholar] [CrossRef]
- Cheng, B.; Ma, J.; Yang, Y.; Shao, T.; Zhao, B.; Zeng, L. Systemic Corticosteroid Administration in Coronavirus Disease 2019 Outcomes: An Umbrella Meta-Analysis Incorporating Both Mild and Pulmonary Fibrosis-Manifested Severe Disease. Front. Pharmacol. 2021, 12, 670170. [Google Scholar] [CrossRef]
- Wagner, C.; Griesel, M.; Mikolajewska, A.; Metzendorf, M.I.; Fischer, A.L.; Stegemann, M.; Spagl, M.; Nair, A.A.; Daniel, J.; Fichtner, F.; et al. Systemic corticosteroids for the treatment of COVID-19: Equity-related analyses and update on evidence. Cochrane Database Syst. Rev. 2022, 11, CD014963. [Google Scholar] [CrossRef]
- Torres, A.; Motos, A.; Cilloniz, C.; Ceccato, A.; Fernandez-Barat, L.; Gabarrus, A.; Bermejo-Martin, J.; Ferrer, R.; Riera, J.; Perez-Arnal, R.; et al. Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study. Intensive Care Med. 2022, 48, 850–864. [Google Scholar] [CrossRef]
- Mustafa, S.S. Steroid induced secondary immune deficiency. Ann. Allergy Asthma Immunol. 2023. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Conti, P. Dexamethasone for COVID-19? Not so fast. J. Biol. Regul. Homeost. Agents 2020, 34, 1241–1243. [Google Scholar] [CrossRef] [PubMed]
- Middleton, E., Jr.; Kandaswami, C.; Theoharides, T.C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 2000, 52, 673–751. [Google Scholar] [PubMed]
- Leyva-Lopez, N.; Gutierrez-Grijalva, E.P.; mbriz-Perez, D.L.; Heredia, J.B. Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases 1. Int. J. Mol. Sci. 2016, 17, 921. [Google Scholar] [CrossRef] [PubMed]
- Jager, A.K.; Saaby, L. Flavonoids and the CNS. Molecules 2011, 16, 1471–1485. [Google Scholar] [CrossRef] [Green Version]
- Calfio, C.; Gonzalez, A.; Singh, S.K.; Rojo, L.E.; Maccioni, R.B. The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease. J. Alzheimers Dis. 2020, 77, 33–51. [Google Scholar] [CrossRef]
- Kempuraj, D.; Thangavel, R.; Kempuraj, D.D.; Ahmed, M.E.; Selvakumar, G.P.; Raikwar, S.P.; Zaheer, S.A.; Iyer, S.S.; Govindarajan, R.; Chandrasekaran, P.N.; et al. Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma. Biofactors 2021, 47, 190–197. [Google Scholar] [CrossRef] [PubMed]
- Calis, Z.; Mogulkoc, R.; Baltaci, A.K. The Roles of Flavonols/Flavonoids in Neurodegeneration and Neuroinflammation. Mini Rev. Med. Chem. 2020, 20, 1475–1488. [Google Scholar] [CrossRef]
- Rezai-Zadeh, K.; Ehrhart, J.; Bai, Y.; Sanberg, P.R.; Bickford, P.; Tan, J.; Shytle, R.D. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J. Neuroinflamm. 2008, 5, 41. [Google Scholar] [CrossRef] [Green Version]
- Jang, S.; Kelley, K.W.; Johnson, R.W. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc. Natl. Acad. Sci. USA 2008, 105, 7534–7539. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weng, Z.; Patel, A.B.; Panagiotidou, S.; Theoharides, T.C. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J. Allergy Clin. Immunol. 2015, 135, 1044–1052. [Google Scholar] [CrossRef] [Green Version]
- Seelinger, G.; Merfort, I.; Schempp, C.M. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med. 2008, 74, 1667–1677. [Google Scholar] [CrossRef] [PubMed]
- Theoharides, T.C.; Conti, P.; Economu, M. Brain inflammation, neuropsychiatric disorders, and immunoendocrine effects of luteolin. J. Clin. Psychopharmacol. 2014, 34, 187–189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ashaari, Z.; Hadjzadeh, M.A.; Hassanzadeh, G.; Alizamir, T.; Yousefi, B.; Keshavarzi, Z.; Mokhtari, T. The Flavone Luteolin Improves Central Nervous System Disorders by Different Mechanisms: A Review. J. Mol. Neurosci. 2018, 65, 491–506. [Google Scholar] [CrossRef] [PubMed]
- Dajas, F.; Rivera-Megret, F.; Blasina, F.; Arredondo, F.; bin-Carriquiry, J.A.; Costa, G.; Echeverry, C.; Lafon, L.; Heizen, H.; Ferreira, M.; et al. Neuroprotection by flavonoids 1. Braz. J. Med. Biol. Res. 2003, 36, 1613–1620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, T.Y.; Lu, C.W.; Wang, S.J. Luteolin protects the hippocampus against neuron impairments induced by kainic acid in rats. NeuroToxicology 2016, 55, 48–57. [Google Scholar] [CrossRef]
- Zhu, L.H.; Bi, W.; Qi, R.B.; Wang, H.D.; Lu, D.X. Luteolin inhibits microglial inflammation and improves neuron survival against inflammation. Int. J. Neurosci. 2011, 121, 329–336. [Google Scholar] [CrossRef]
- Rezai-Zadeh, K.; Douglas, S.R.; Bai, Y.; Tian, J.; Hou, H.; Mori, T.; Zeng, J.; Obregon, D.; Town, T.; Tan, J. Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer’s disease beta-amyloid production. J. Cell. Mol. Med. 2009, 13, 574–588. [Google Scholar] [CrossRef]
- Yao, Z.H.; Yao, X.L.; Zhang, Y.; Zhang, S.F.; Hu, J.C. Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation. Neurochem. Res. 2018, 43, 806–820. [Google Scholar] [CrossRef]
- Gratton, G.; Weaver, S.R.; Burley, C.V.; Low, K.A.; Maclin, E.L.; Johns, P.W.; Pham, Q.S.; Lucas, S.J.E.; Fabiani, M.; Rendeiro, C. Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults. Sci. Rep. 2020, 10, 19409. [Google Scholar] [CrossRef] [PubMed]
- Devi, S.A.; Chamoli, A. Polyphenols as an Effective Therapeutic Intervention Against Cognitive Decline During Normal and Pathological Brain Aging. Adv. Exp. Med. Biol. 2020, 1260, 159–174. [Google Scholar] [PubMed]
- Theoharides, T.C.; Stewart, J.M.; Hatziagelaki, E.; Kolaitis, G. Brain “fog,” inflammation and obesity: Key aspects of 2 neuropsychiatric disorders improved by luteolin. Front. Neurosci. 2015, 9, 225. [Google Scholar] [CrossRef] [Green Version]
- Stefano, G.B.; Buttiker, P.; Weissenberger, S.; Martin, A.; Ptacek, R.; Kream, R.M. Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis. Med. Sci. Monit. 2021, 27, e933015. [Google Scholar] [CrossRef]
- Hugon, J.; Msika, E.F.; Queneau, M.; Farid, K.; Paquet, C. Long COVID: Cognitive complaints (brain fog) and dysfunction of the cingulate cortex. J. Neurol. 2022, 269, 44–46. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Guerra, L.; Patel, K. Successful Treatment of a Patient With Severe COVID-19 Using an Integrated Approach Addressing Mast Cells and Their Mediators. Int. J. Infect. Dis. 2022, 118, 164–166. [Google Scholar] [CrossRef]
- Islam, A.; Islam, M.S.; Rahman, M.K.; Uddin, M.N.; Akanda, M.R. The pharmacological and biological roles of eriodictyol. Arch. Pharm. Res. 2020, 43, 582–592. [Google Scholar] [CrossRef]
- Zhang, L.; Liu, C.; Yuan, M. Eriodictyol produces antidepressant-like effects and ameliorates cognitive impairments induced by chronic stress. Neuroreport 2020, 31, 1111–1120. [Google Scholar] [CrossRef]
- Deng, Z.; Hassan, S.; Rafiq, M.; Li, H.; He, Y.; Cai, Y.; Kang, X.; Liu, Z.; Yan, T. Pharmacological Activity of Eriodictyol: The Major Natural Polyphenolic Flavanone. Evid. Based. Complement. Alternat. Med. 2020, 2020, 6681352. [Google Scholar] [CrossRef]
- Mokdad-Bzeouich, I.; Mustapha, N.; Sassi, A.; Bedoui, A.; Ghoul, M.; Ghedira, K.; Chekir-Ghedira, L. Investigation of immunomodulatory and anti-inflammatory effects of eriodictyol through its cellular anti-oxidant activity. Cell Stress Chaperones 2016, 21, 773–781. [Google Scholar] [CrossRef] [Green Version]
- Deshpande, R.R.; Tiwari, A.P.; Nyayanit, N.; Modak, M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur. J. Pharmacol. 2020, 886, 173430. [Google Scholar] [CrossRef] [PubMed]
- Rudrapal, M.; Issahaku, A.R.; Agoni, C.; Bendale, A.R.; Nagar, A.; Soliman, M.E.S.; Lokwani, D. In silico screening of phytopolyphenolics for the identification of bioactive compounds as novel protease inhibitors effective against SARS-CoV-2. J. Biomol. Struct. Dyn. 2022, 40, 10437–10453. [Google Scholar] [CrossRef]
- Ton, A.T.; Gentile, F.; Hsing, M.; Ban, F.; Cherkasov, A. Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds. Mol. Inform. 2020, 39, e2000028. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gentile, F.; Fernandez, M.; Ban, F.; Ton, A.T.; Mslati, H.; Perez, C.F.; Leblanc, E.; Yaacoub, J.C.; Gleave, J.; Stern, A.; et al. Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules. Chem. Sci. 2021, 12, 15960–15974. [Google Scholar] [CrossRef]
- Vijayan, R.; Gourinath, S. Structure-based inhibitor screening of natural products against NSP15 of SARS-CoV-2 revealed thymopentin and oleuropein as potent inhibitors. J. Proteins Proteom. 2021, 12, 71–80. [Google Scholar] [CrossRef]
- Abdelgawad, S.M.; Hassab, M.A.E.; Abourehab, M.A.S.; Elkaeed, E.B.; Eldehna, W.M. Olive Leaves as a Potential Phytotherapy in the Treatment of COVID-19 Disease; A Mini-Review. Front. Pharmacol. 2022, 13, 879118. [Google Scholar] [CrossRef] [PubMed]
- Geromichalou, E.G.; Geromichalos, G.D. In Silico Approach for the Evaluation of the Potential Antiviral Activity of Extra Virgin Olive Oil (EVOO) Bioactive Constituents Oleuropein and Oleocanthal on Spike Therapeutic Drug Target of SARS-CoV-2. Molecules 2022, 27, 7572. [Google Scholar] [CrossRef] [PubMed]
- Ordonez, A.A.; Bullen, C.K.; Villabona-Rueda, A.F.; Thompson, E.A.; Turner, M.L.; Merino, V.F.; Yan, Y.; Kim, J.; Davis, S.L.; Komm, O.; et al. Sulforaphane exhibits antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses in vitro and in mice. Commun. Biol. 2022, 5, 242. [Google Scholar] [CrossRef]
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Theoharides, T.C.; Kempuraj, D. Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Cells 2023, 12, 688. https://doi.org/10.3390/cells12050688
Theoharides TC, Kempuraj D. Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Cells. 2023; 12(5):688. https://doi.org/10.3390/cells12050688
Chicago/Turabian StyleTheoharides, Theoharis C., and Duraisamy Kempuraj. 2023. "Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID" Cells 12, no. 5: 688. https://doi.org/10.3390/cells12050688
APA StyleTheoharides, T. C., & Kempuraj, D. (2023). Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Cells, 12(5), 688. https://doi.org/10.3390/cells12050688