Connexin 43: An Interface Connecting Neuroinflammation to Depression
Abstract
:1. Introduction
2. Association between Cx43 and Inflammation
2.1. Cx43 Gap Junction Channels and Cx43 Hemichannels
2.2. Function of Cx43 in Neuroinflammation
2.2.1. Astrocytes
2.2.2. Microglia
2.2.3. Immune Cells
2.2.4. Endothelial Cells
3. The Cornerstones Linking Inflammation and Depression
3.1. Clinical Evidence
3.1.1. Increased Inflammatory Response in Patients with Depression
3.1.2. High Comorbidity Rate of Depression and Multiple Immune-Based Diseases
3.1.3. Inflammatory Factors Induce Depression
3.2. Experimental Evidence
4. Cx43 Abnormalities and Dysfunction in Depression
5. Cx43 as a Mediator of Neuroinflammation and Depression
5.1. Regulation of Cx43 by Inflammatory Cytokines in Depression
5.2. Cx43 in Treatment-Resistant Depression and Neuroinflammation
5.3. Effects of Antidepressants and Anti-Inflammatory Drugs on Cx43
5.3.1. Antidepressants
5.3.2. Anti-Inflammatory Drugs
5.4. Pathogenesis Associated with Cx43 and Neuroinflammation
5.4.1. ATP Release
5.4.2. Glutamate–Glutamine Cycle
6. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Zhang, X.; Wang, P.; Shi, L.; Li, N. Study on caspase-1 and partial cognitive impairment in the comorbidity of type 2 diabetes and MDD. J. Affect. Disord. 2021, 290, 387–392. [Google Scholar] [CrossRef]
- Xia, C.Y.; Wang, Z.Z.; Yamakuni, T.; Chen, N.H. A novel mechanism of depression: Role for connexins. Eur. Neuropsychopharmacol. 2018, 28, 483–498. [Google Scholar] [CrossRef] [PubMed]
- Foster, J.A.; Baker, G.B.; Dursun, S.M. The Relationship Between the Gut Microbiome-Immune System-Brain Axis and Major Depressive Disorder. Front. Neurol. 2021, 12, 721126. [Google Scholar] [CrossRef] [PubMed]
- Solan, J.L.; Lampe, P.D. Src Regulation of Cx43 Phosphorylation and Gap Junction Turnover. Biomolecules 2020, 10, 1596. [Google Scholar] [CrossRef] [PubMed]
- Okada, M.; Fukuyama, K.; Shiroyama, T.; Murata, M. A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43. Int. J. Mol. Sci. 2020, 21, 7019. [Google Scholar] [CrossRef] [PubMed]
- Zhang, N.N.; Zhang, Y.; Wang, Z.Z.; Chen, N.H. Connexin 43: Insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy. Acta Pharmacol. Sin. 2022, 43, 2448–2461. [Google Scholar] [CrossRef]
- Chen, M.J.; Kress, B.; Han, X.; Moll, K.; Peng, W.; Ji, R.R.; Nedergaard, M. Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury. Glia 2012, 60, 1660–1670. [Google Scholar] [CrossRef] [Green Version]
- Lanciotti, A.; Brignone, M.S.; Belfiore, M.; Columba-Cabezas, S.; Mallozzi, C.; Vincentini, O.; Molinari, P.; Petrucci, T.C.; Visentin, S.; Ambrosini, E. Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes. Cells 2020, 9, 1425. [Google Scholar] [CrossRef]
- Solan, J.L.; Lampe, P.D. Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics. Biochim. Biophys. Acta Biomembr. 2018, 1860, 83–90. [Google Scholar] [CrossRef]
- Harris, A.L. Emerging issues of connexin channels: Biophysics fills the gap. Q. Rev. Biophys. 2001, 34, 325–472. [Google Scholar] [CrossRef]
- Zheng, L.; Li, H.; Cannon, A.; Trease, A.J.; Spagnol, G.; Zheng, H.; Radio, S.; Patel, K.; Batra, S.; Sorgen, P.L. Phosphorylation of Cx43 residue Y313 by Src contributes to blocking the interaction with Drebrin and disassembling gap junctions. J. Mol. Cell. Cardiol. 2019, 126, 36–49. [Google Scholar] [CrossRef] [PubMed]
- Solan, J.L.; Márquez-Rosado, L.; Lampe, P.D. Cx43 phosphorylation-mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter the stability of the stress-inducible protein NDRG1. J. Biol. Chem. 2019, 294, 11762–11771. [Google Scholar] [CrossRef] [PubMed]
- Solan, J.L.; Lampe, P.D. Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett. 2014, 588, 1423–1429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Orellana, J.A.; Martinez, A.D.; Retamal, M.A. Gap junction channels and hemichannels in the CNS: Regulation by signaling molecules. Neuropharmacology 2013, 75, 567–582. [Google Scholar] [CrossRef] [PubMed]
- Ji, R.R.; Xu, Z.Z.; Gao, Y.J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 2014, 13, 533–548. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Matsuda, M.; Huh, Y.; Ji, R.R. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J. Anesth. 2019, 33, 131–139. [Google Scholar] [CrossRef]
- Holmes, C. Review: Systemic inflammation and Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 2013, 39, 51–68. [Google Scholar] [CrossRef]
- Devinsky, O.; Vezzani, A.; Najjar, S.; De Lanerolle, N.C.; Rogawski, M.A. Glia and epilepsy: Excitability and inflammation. Trends Neurosci. 2013, 36, 174–184. [Google Scholar] [CrossRef]
- Marogianni, C.; Sokratous, M.; Dardiotis, E.; Hadjigeorgiou, G.M.; Bogdanos, D.; Xiromerisiou, G. Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 8421. [Google Scholar] [CrossRef]
- Kohler, O.; Krogh, J.; Mors, O.; Benros, M.E. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr. Neuropharmacol. 2016, 14, 732–742. [Google Scholar] [CrossRef]
- Nettis, M.A.; Pariante, C.M. Is there neuroinflammation in depression? Understanding the link between the brain and the peripheral immune system in depression. Int. Rev. Neurobiol. 2020, 152, 23–40. [Google Scholar] [CrossRef] [PubMed]
- Huang, X.; Hussain, B.; Chang, J. Peripheral inflammation and blood-brain barrier disruption: Effects and mechanisms. CNS Neurosci. Ther. 2021, 27, 36–47. [Google Scholar] [CrossRef] [PubMed]
- Hansson, E.; Skioldebrand, E. Coupled cell networks are target cells of inflammation, which can spread between different body organs and develop into systemic chronic inflammation. J. Inflamm. 2015, 12, 44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Denes, A.; Thornton, P.; Rothwell, N.J.; Allan, S.M. Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation. Brain Behav. Immun. 2010, 24, 708–723. [Google Scholar] [CrossRef] [PubMed]
- Abbott, N.J.; Rönnbäck, L.; Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006, 7, 41–53. [Google Scholar] [CrossRef]
- Portal, B.; Delcourte, S.; Rovera, R.; Lejards, C.; Bullich, S.; Malnou, C.E.; Haddjeri, N.; Déglon, N.; Guiard, B.P. Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs. Acta Physiol. 2020, 229, e13440. [Google Scholar] [CrossRef]
- Yang, Q.Q.; Zhou, J.W. Neuroinflammation in the central nervous system: Symphony of glial cells. Glia 2019, 67, 1017–1035. [Google Scholar] [CrossRef]
- Sarrouilhe, D.; Dejean, C.; Mesnil, M. Connexin43- and Pannexin-Based Channels in Neuroinflammation and Cerebral Neuropathies. Front. Mol. Neurosci. 2017, 10, 320. [Google Scholar] [CrossRef]
- Kajiwara, Y.; Wang, E.; Wang, M.; Sin, W.C.; Brennand, K.J.; Schadt, E.; Naus, C.C.; Buxbaum, J.; Zhang, B. GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis. Acta Neuropathol. Commun. 2018, 6, 144. [Google Scholar] [CrossRef] [Green Version]
- Minter, M.R.; Taylor, J.M.; Crack, P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem. 2016, 136, 457–474. [Google Scholar] [CrossRef]
- Brod, S.A. Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease. J. Alzheimers Dis. 2022, 85, 457–472. [Google Scholar] [CrossRef]
- Xie, H.Y.; Cui, Y.; Deng, F.; Feng, J.C. Connexin: A potential novel target for protecting the central nervous system? Neural. Regen. Res. 2015, 10, 659–666. [Google Scholar] [CrossRef] [PubMed]
- Kamaşak, T.; Dilber, B.; Yaman, S.; Durgut, B.D.; Kurt, T.; Çoban, E.; Arslan, E.A.; Şahin, S.; Karahan, S.C.; Cansu, A. HMGB-1, TLR4, IL-1R1, TNF-α, and IL-1β: Novel epilepsy markers? Epileptic Disord. 2020, 22, 183–193. [Google Scholar] [CrossRef] [PubMed]
- Uludag, I.F.; Duksal, T.; Tiftikcioglu, B.I.; Zorlu, Y.; Ozkaya, F.; Kirkali, G. IL-1β, IL-6 and IL1Ra levels in temporal lobe epilepsy. Seizure 2015, 26, 22–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khosla, K.; Naus, C.C.; Sin, W.C. Cx43 in Neural Progenitors Promotes Glioma Invasion in a 3D Culture System. Int. J. Mol. Sci. 2020, 21, 5216. [Google Scholar] [CrossRef] [PubMed]
- Uzu, M.; Sin, W.C.; Shimizu, A.; Sato, H. Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System. Int. J. Mol. Sci. 2018, 19, 1159. [Google Scholar] [CrossRef] [Green Version]
- Zhou, W.; Jiang, Z.; Li, X.; Xu, Y.; Shao, Z. Cytokines: Shifting the balance between glioma cells and tumor microenvironment after irradiation. J. Cancer Res. Clin. Oncol. 2015, 141, 575–589. [Google Scholar] [CrossRef]
- Liang, Z.; Wang, X.; Hao, Y.; Qiu, L.; Lou, Y.; Zhang, Y.; Ma, D.; Feng, J. The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions. Front. Neurol. 2020, 11, 703. [Google Scholar] [CrossRef]
- Wu, L.Y.; Yu, X.L.; Feng, L.Y. Connexin 43 stabilizes astrocytes in a stroke-like milieu to facilitate neuronal recovery. Acta Pharmacol. Sin. 2015, 36, 928–938. [Google Scholar] [CrossRef]
- Glass, C.K.; Saijo, K.; Winner, B.; Marchetto, M.C.; Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140, 918–934. [Google Scholar] [CrossRef]
- Leng, F.; Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nat. Rev. Neurol. 2021, 17, 157–172. [Google Scholar] [CrossRef] [PubMed]
- Belousov, A.B.; Fontes, J.D.; Freitas-Andrade, M.; Naus, C.C. Gap junctions and hemichannels: Communicating cell death in neurodevelopment and disease. BMC Cell Biol. 2017, 18, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Retamal, M.A.; Froger, N.; Palacios-Prado, N.; Ezan, P.; Saez, P.J.; Saez, J.C.; Giaume, C. Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J. Neurosci. 2007, 27, 13781–13792. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karpuk, N.; Burkovetskaya, M.; Fritz, T.; Angle, A.; Kielian, T. Neuroinflammation leads to region-dependent alterations in astrocyte gap junction communication and hemichannel activity. J. Neurosci. 2011, 31, 414–425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Basu, R.; Banerjee, K.; Bose, A.; Das Sarma, J. Mouse Hepatitis Virus Infection Remodels Connexin43-Mediated Gap Junction Intercellular Communication In Vitro and In Vivo. J. Virol. 2015, 90, 2586–2599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, F.F.; Morioka, N.; Kitamura, T.; Hisaoka-Nakashima, K.; Nakata, Y. Proinflammatory cytokines downregulate connexin 43-gap junctions via the ubiquitin-proteasome system in rat spinal astrocytes. Biochem. Biophys. Res. Commun. 2015, 464, 1202–1208. [Google Scholar] [CrossRef]
- Lampe, P.D.; TenBroek, E.M.; Burt, J.M.; Kurata, W.E.; Johnson, R.G.; Lau, A.F. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J. Cell. Biol. 2000, 149, 1503–1512. [Google Scholar] [CrossRef]
- Gomez, G.I.; Falcon, R.V.; Maturana, C.J.; Labra, V.C.; Salgado, N.; Rojas, C.A.; Oyarzun, J.E.; Cerpa, W.; Quintanilla, R.A.; Orellana, J.A. Heavy Alcohol Exposure Activates Astroglial Hemichannels and Pannexons in the Hippocampus of Adolescent Rats: Effects on Neuroinflammation and Astrocyte Arborization. Front. Cell Neurosci. 2018, 12, 472. [Google Scholar] [CrossRef]
- Abudara, V.; Roux, L.; Dallerac, G.; Matias, I.; Dulong, J.; Mothet, J.P.; Rouach, N.; Giaume, C. Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes. Glia 2015, 63, 795–811. [Google Scholar] [CrossRef]
- Li, H.; Liu, T.F.; Lazrak, A.; Peracchia, C.; Goldberg, G.S.; Lampe, P.D.; Johnson, R.G. Properties and regulation of gap junctional hemichannels in the plasma membranes of cultured cells. J. Cell Biol. 1996, 134, 1019–1030. [Google Scholar] [CrossRef]
- Orellana, J.A.; Hernández, D.E.; Ezan, P.; Velarde, V.; Bennett, M.V.; Giaume, C.; Sáez, J.C. Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels. Glia 2010, 58, 329–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Froger, N.; Orellana, J.A.; Calvo, C.F.; Amigou, E.; Kozoriz, M.G.; Naus, C.C.; Sáez, J.C.; Giaume, C. Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective. Mol. Cell Neurosci. 2010, 45, 37–46. [Google Scholar] [CrossRef] [PubMed]
- Mei, X.; Ezan, P.; Giaume, C.; Koulakoff, A. Astroglial connexin immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice. Neuroscience 2010, 171, 92–105. [Google Scholar] [CrossRef]
- Haghikia, A.; Ladage, K.; Lafenetre, P.; Haghikia, A.; Hinkerohe, D.; Smikalla, D.; Haase, C.G.; Dermietzel, R.; Faustmann, P.M. Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells. J. Neurooncol. 2008, 86, 143–152. [Google Scholar] [CrossRef]
- Wang, X.; Feng, L.; Xin, M.; Hao, Y.; Wang, X.; Shang, P.; Zhao, M.; Hou, S.; Zhang, Y.; Xiao, Y.; et al. Mechanisms underlying astrocytic connexin-43 autophagy degradation during cerebral ischemia injury and the effect on neuroinflammation and cell apoptosis. Biomed. Pharmacother. 2020, 127, 110125. [Google Scholar] [CrossRef] [PubMed]
- Tonkin, R.S.; Bowles, C.; Perera, C.J.; Keating, B.A.; Makker, P.G.S.; Duffy, S.S.; Lees, J.G.; Tran, C.; Don, A.S.; Fath, T.; et al. Attenuation of mechanical pain hypersensitivity by treatment with Peptide5, a connexin-43 mimetic peptide, involves inhibition of NLRP3 inflammasome in nerve-injured mice. Exp. Neurol. 2018, 300, 1–12. [Google Scholar] [CrossRef]
- Zgorzynska, E.; Dziedzic, B.; Markiewicz, M.; Walczewska, A. Omega-3 PUFAs Suppress IL-1beta-Induced Hyperactivity of Immunoproteasomes in Astrocytes. Int. J. Mol. Sci. 2021, 22, 5410. [Google Scholar] [CrossRef]
- Orellana, J.A.; Froger, N.; Ezan, P.; Jiang, J.X.; Bennett, M.V.; Naus, C.C.; Giaume, C.; Sáez, J.C. ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. J. Neurochem. 2011, 118, 826–840. [Google Scholar] [CrossRef] [Green Version]
- Rochefort, N.; Quenech’du, N.; Watroba, L.; Mallat, M.; Giaume, C.; Milleret, C. Microglia and astrocytes may participate in the shaping of visual callosal projections during postnatal development. J. Physiol. Paris 2002, 96, 183–192. [Google Scholar] [CrossRef]
- Watanabe, M.; Masaki, K.; Yamasaki, R.; Kawanokuchi, J.; Takeuchi, H.; Matsushita, T.; Suzumura, A.; Kira, J.I. Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation. Sci. Rep. 2016, 6, 38387. [Google Scholar] [CrossRef]
- Bhowmick, S.; D’Mello, V.; Caruso, D.; Wallerstein, A.; Abdul-Muneer, P.M. Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury. Exp. Neurol. 2019, 317, 260–270. [Google Scholar] [CrossRef] [PubMed]
- Cibelli, A.; Stout, R.; Timmermann, A.; de Menezes, L.; Guo, P.; Maass, K.; Seifert, G.; Steinhauser, C.; Spray, D.C.; Scemes, E. Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability. Sci. Rep. 2021, 11, 24334. [Google Scholar] [CrossRef] [PubMed]
- Han, Y.; Yu, H.X.; Sun, M.L.; Wang, Y.; Xi, W.; Yu, Y.Q. Astrocyte-restricted disruption of connexin-43 impairs neuronal plasticity in mouse barrel cortex. Eur. J. Neurosci. 2014, 39, 35–45. [Google Scholar] [CrossRef] [PubMed]
- Boulay, A.C.; Cisternino, S.; Cohen-Salmon, M. Immunoregulation at the gliovascular unit in the healthy brain: A focus on Connexin 43. Brain Behav. Immun. 2016, 56, 1–9. [Google Scholar] [CrossRef] [PubMed]
- D’Mello, C.; Swain, M.G. Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression. Curr. Top. Behav. Neurosci. 2017, 31, 73–94. [Google Scholar] [CrossRef] [PubMed]
- Liddelow, S.A.; Guttenplan, K.A.; Clarke, L.E.; Bennett, F.C.; Bohlen, C.J.; Schirmer, L.; Bennett, M.L.; Munch, A.E.; Chung, W.S.; Peterson, T.C.; et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017, 541, 481–487. [Google Scholar] [CrossRef] [Green Version]
- Ma, Y.; Bu, J.; Dang, H.; Sha, J.; Jing, Y.; Shan-jiang, A.I.; Li, H.; Zhu, Y. Inhibition of adenosine monophosphate-activated protein kinase reduces glial cell-mediated inflammation and induces the expression of Cx43 in astroglias after cerebral ischemia. Brain Res. 2015, 1605, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Koulakoff, A.; Mei, X.; Orellana, J.A.; Saez, J.C.; Giaume, C. Glial connexin expression and function in the context of Alzheimer’s disease. Biochim. Biophys. Acta 2012, 1818, 2048–2057. [Google Scholar] [CrossRef] [Green Version]
- Eugenín, E.A.; Eckardt, D.; Theis, M.; Willecke, K.; Bennett, M.V.; Saez, J.C. Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-gamma and tumor necrosis factor-alpha. Proc. Natl. Acad. Sci. USA 2001, 98, 4190–4195. [Google Scholar] [CrossRef] [Green Version]
- Singh, S.; Swarnkar, S.; Goswami, P.; Nath, C. Astrocytes and microglia: Responses to neuropathological conditions. Int. J. Neurosci. 2011, 121, 589–597. [Google Scholar] [CrossRef]
- Keller, A.F.; Gravel, M.; Kriz, J. Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice. Exp. Neurol. 2011, 228, 69–79. [Google Scholar] [CrossRef] [PubMed]
- Orellana, J.A.; Shoji, K.F.; Abudara, V.; Ezan, P.; Amigou, E.; Saez, P.J.; Jiang, J.X.; Naus, C.C.; Saez, J.C.; Giaume, C. Amyloid beta-induced death in neurons involves glial and neuronal hemichannels. J. Neurosci. 2011, 31, 4962–4977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Même, W.; Calvo, C.F.; Froger, N.; Ezan, P.; Amigou, E.; Koulakoff, A.; Giaume, C. Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: Potentiation by beta-amyloid. FASEB J. 2006, 20, 494–496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Faustmann, P.M.; Haase, C.G.; Romberg, S.; Hinkerohe, D.; Szlachta, D.; Smikalla, D.; Krause, D.; Dermietzel, R. Microglia activation influences dye coupling and Cx43 expression of the astrocytic network. Glia 2003, 42, 101–108. [Google Scholar] [CrossRef] [PubMed]
- Hinkerohe, D.; Smikalla, D.; Haghikia, A.; Heupel, K.; Haase, C.G.; Dermietzel, R.; Faustmann, P.M. Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model. Glia 2005, 52, 85–97. [Google Scholar] [CrossRef] [PubMed]
- Hinkerohe, D.; Smikalla, D.; Schoebel, A.; Haghikia, A.; Zoidl, G.; Haase, C.G.; Schlegel, U.; Faustmann, P.M. Dexamethasone prevents LPS-induced microglial activation and astroglial impairment in an experimental bacterial meningitis co-culture model. Brain Res. 2010, 1329, 45–54. [Google Scholar] [CrossRef] [PubMed]
- Orellana, J.A.; von Bernhardi, R.; Giaume, C.; Saez, J.C. Glial hemichannels and their involvement in aging and neurodegenerative diseases. Rev. Neurosci. 2012, 23, 163–177. [Google Scholar] [CrossRef]
- Ma, Y.; Cao, W.; Wang, L.; Jiang, J.; Nie, H.; Wang, B.; Wei, X.; Ying, W. Basal CD38/cyclic ADP-ribose-dependent signaling mediates ATP release and survival of microglia by modulating connexin 43 hemichannels. Glia 2014, 62, 943–955. [Google Scholar] [CrossRef]
- Solleiro-Villavicencio, H.; Rivas-Arancibia, S. Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4(+)T Cells in Neurodegenerative Diseases. Front. Cell. Neurosci. 2018, 12, 114. [Google Scholar] [CrossRef] [Green Version]
- Alves, L.A.; de Carvalho, A.C.; Savino, W. Gap junctions: A novel route for direct cell-cell communication in the immune system? Immunol. Today 1998, 19, 269–275. [Google Scholar] [CrossRef]
- Bermudez-Fajardo, A.; Yliharsila, M.; Evans, W.H.; Newby, A.C.; Oviedo-Orta, E. CD4+ T lymphocyte subsets express connexin 43 and establish gap junction channel communication with macrophages in vitro. J. Leukoc. Biol. 2007, 82, 608–612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oviedo-Orta, E.; Errington, R.J.; Evans, W.H. Gap junction intercellular communication during lymphocyte transendothelial migration. Cell Biol. Int. 2002, 26, 253–263. [Google Scholar] [CrossRef] [PubMed]
- Boulay, A.C.; Mazeraud, A.; Cisternino, S.; Saubamea, B.; Mailly, P.; Jourdren, L.; Blugeon, C.; Mignon, V.; Smirnova, M.; Cavallo, A.; et al. Immune quiescence of the brain is set by astroglial connexin 43. J. Neurosci. 2015, 35, 4427–4439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Holling, T.M.; Schooten, E.; van Den Elsen, P.J. Function and regulation of MHC class II molecules in T-lymphocytes: Of mice and men. Hum. Immunol. 2004, 65, 282–290. [Google Scholar] [CrossRef]
- Eugenin, E.A.; Branes, M.C.; Berman, J.W.; Saez, J.C. TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J. Immunol. 2003, 170, 1320–1328. [Google Scholar] [CrossRef] [Green Version]
- Eltzschig, H.K.; Eckle, T.; Mager, A.; Kuper, N.; Karcher, C.; Weissmuller, T.; Boengler, K.; Schulz, R.; Robson, S.C.; Colgan, S.P. ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ. Res. 2006, 99, 1100–1108. [Google Scholar] [CrossRef] [Green Version]
- Chen, Q.; Boire, A.; Jin, X.; Valiente, M.; Er, E.E.; Lopez-Soto, A.; Jacob, L.; Patwa, R.; Shah, H.; Xu, K.; et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 2016, 533, 493–498. [Google Scholar] [CrossRef] [Green Version]
- Oviedo-Orta, E.; Perreau, M.; Evans, W.H.; Potolicchio, I. Control of the proliferation of activated CD4+ T cells by connexins. J. Leukoc. Biol. 2010, 88, 79–86. [Google Scholar] [CrossRef]
- Zhang, L.; Fan, Z.R.; Wang, L.; Liu, L.Q.; Li, X.Z.; Li, L.; Si, J.Q.; Ma, K.T. Carbenoxolone decreases monocrotaline-induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes. Int. J. Mol. Med. 2020, 45, 81–92. [Google Scholar] [CrossRef] [Green Version]
- Ji, H.; Qiu, R.; Gao, X.; Zhang, R.; Li, X.; Hei, Z.; Yuan, D. Propofol attenuates monocyte-endothelial adhesion via modulating connexin43 expression in monocytes. Life Sci. 2019, 232, 116624. [Google Scholar] [CrossRef]
- Willebrords, J.; Crespo Yanguas, S.; Maes, M.; Decrock, E.; Wang, N.; Leybaert, L.; Kwak, B.R.; Green, C.R.; Cogliati, B.; Vinken, M. Connexins and their channels in inflammation. Crit. Rev. Biochem. Mol. Biol. 2016, 51, 413–439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berezowski, V.; Fukuda, A.M.; Cecchelli, R.; Badaut, J. Endothelial cells and astrocytes: A concerto en duo in ischemic pathophysiology. Int. J. Cell Biol. 2012, 2012, 176287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramadan, R.; Vromans, E.; Anang, D.C.; Goetschalckx, I.; Hoorelbeke, D.; Decrock, E.; Baatout, S.; Leybaert, L.; Aerts, A. Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage. Front. Pharmacol. 2020, 11, 212. [Google Scholar] [CrossRef] [PubMed]
- Wilson, A.C.; Clemente, L.; Liu, T.; Bowen, R.L.; Meethal, S.V.; Atwood, C.S. Reproductive hormones regulate the selective permeability of the blood-brain barrier. Biochim. Biophys. Acta 2008, 1782, 401–407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Bock, M.; Wang, N.; Decrock, E.; Bultynck, G.; Leybaert, L. Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation? Mediat. Inflamm. 2015, 2015, 257471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Johnson, A.M.; Roach, J.P.; Hu, A.; Stamatovic, S.M.; Zochowski, M.R.; Keep, R.F.; Andjelkovic, A.V. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure. FASEB J. 2018, 32, 2615–2629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kurmann, L.; Okoniewski, M.; Dubey, R.K. Transcryptomic Analysis of Human Brain -Microvascular Endothelial Cell Driven Changes in -Vascular Pericytes. Cells 2021, 10, 1784. [Google Scholar] [CrossRef]
- De Bock, M.; Wang, N.; Decrock, E.; Bol, M.; Gadicherla, A.K.; Culot, M.; Cecchelli, R.; Bultynck, G.; Leybaert, L. Endothelial calcium dynamics, connexin channels and blood-brain barrier function. Prog. Neurobiol. 2013, 108, 1–20. [Google Scholar] [CrossRef]
- Ezan, P.; Andre, P.; Cisternino, S.; Saubamea, B.; Boulay, A.C.; Doutremer, S.; Thomas, M.A.; Quenech’du, N.; Giaume, C.; Cohen-Salmon, M. Deletion of astroglial connexins weakens the blood-brain barrier. J. Cereb. Blood Flow Metab. 2012, 32, 1457–1467. [Google Scholar] [CrossRef] [Green Version]
- Lutz, S.E.; Raine, C.S.; Brosnan, C.F. Loss of astrocyte connexins 43 and 30 does not significantly alter susceptibility or severity of acute experimental autoimmune encephalomyelitis in mice. J. Neuroimmunol. 2012, 245, 8–14. [Google Scholar] [CrossRef]
- Raison, C.L.; Broadwell, S.D.; Borisov, A.S.; Manatunga, A.K.; Capuron, L.; Woolwine, B.J.; Jacobson, I.M.; Nemeroff, C.B.; Miller, A.H. Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C. Brain Behav. Immun. 2005, 19, 23–27. [Google Scholar] [CrossRef] [PubMed]
- Stuve, O.; Zettl, U. Neuroinflammation of the central and peripheral nervous system: An update. Clin. Exp. Immunol. 2014, 175, 333–335. [Google Scholar] [CrossRef] [PubMed]
- Wu, Z.; Xiao, L.; Wang, H.; Wang, G. Neurogenic hypothesis of positive psychology in stress-induced depression: Adult hippocampal neurogenesis, neuroinflammation, and stress resilience. Int. Immunopharmacol. 2021, 97, 107653. [Google Scholar] [CrossRef] [PubMed]
- Eriksson, C.; Nobel, S.; Winblad, B.; Schultzberg, M. Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides. Cytokine 2000, 12, 423–431. [Google Scholar] [CrossRef] [PubMed]
- Leff-Gelman, P.; Mancilla-Herrera, I.; Flores-Ramos, M.; Cruz-Fuentes, C.; Reyes-Grajeda, J.P.; Garcia-Cuetara Mdel, P.; Bugnot-Perez, M.D.; Pulido-Ascencio, D.E. The Immune System and the Role of Inflammation in Perinatal Depression. Neurosci. Bull. 2016, 32, 398–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miller, G.E.; White, S.F.; Chen, E.; Nusslock, R. Association of Inflammatory Activity With Larger Neural Responses to Threat and Reward Among Children Living in Poverty. Am. J. Psychiatry 2021, 178, 313–320. [Google Scholar] [CrossRef]
- Petralia, M.C.; Mazzon, E.; Fagone, P.; Basile, M.S.; Lenzo, V.; Quattropani, M.C.; Di Nuovo, S.; Bendtzen, K.; Nicoletti, F. The cytokine network in the pathogenesis of major depressive disorder. Close to translation? Autoimmun. Rev. 2020, 19, 102504. [Google Scholar] [CrossRef]
- Beurel, E.; Toups, M.; Nemeroff, C.B. The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron 2020, 107, 234–256. [Google Scholar] [CrossRef]
- Slavich, G.M.; Sacher, J. Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders. Psychopharmacology 2019, 236, 3063–3079. [Google Scholar] [CrossRef]
- Ambrosio, G.; Kaufmann, F.N.; Manosso, L.; Platt, N.; Ghisleni, G.; Rodrigues, A.L.S.; Rieger, D.K.; Kaster, M.P. Depression and peripheral inflammatory profile of patients with obesity. Psychoneuroendocrinology 2018, 91, 132–141. [Google Scholar] [CrossRef]
- Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 2009, 65, 732–741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Petralia, M.C.; Mazzon, E.; Fagone, P.; Basile, M.S.; Lenzo, V.; Quattropani, M.C.; Bendtzen, K.; Nicoletti, F. Pathogenic contribution of the Macrophage migration inhibitory factor family to major depressive disorder and emerging tailored therapeutic approaches. J. Affect. Disord. 2020, 263, 15–24. [Google Scholar] [CrossRef] [PubMed]
- Cardinal, P.; Monchaux de Oliveira, C.; Sauvant, J.; Foury, A.; Darnaudery, M.; Vancassel, S.; Castanon, N.; Capuron, L. A new experimental design to study inflammation-related versus non-inflammation-related depression in mice. J. Neuroinflammation 2021, 18, 290. [Google Scholar] [CrossRef]
- Zhou, Y.; Huang, S.; Wu, F.; Zheng, Q.; Zhang, F.; Luo, Y.; Jian, X. Atractylenolide III reduces depressive- and anxiogenic-like behaviors in rat depression models. Neurosci. Lett. 2021, 759, 136050. [Google Scholar] [CrossRef] [PubMed]
- Maldonado-Bouchard, S.; Peters, K.; Woller, S.A.; Madahian, B.; Faghihi, U.; Patel, S.; Bake, S.; Hook, M.A. Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury. Brain Behav. Immun. 2016, 51, 176–195. [Google Scholar] [CrossRef] [Green Version]
- Kelly, J.R.; Borre, Y.; O’Brien, C.; Patterson, E.; El Aidy, S.; Deane, J.; Kennedy, P.J.; Beers, S.; Scott, K.; Moloney, G.; et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 2016, 82, 109–118. [Google Scholar] [CrossRef] [PubMed]
- Zhao, X.; Cao, F.; Liu, Q.; Li, X.; Xu, G.; Liu, G.; Zhang, Y.; Yang, X.; Yi, S.; Xu, F.; et al. Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression. Behav. Brain Res. 2019, 364, 494–502. [Google Scholar] [CrossRef]
- Nagy, C.; Torres-Platas, S.G.; Mechawar, N.; Turecki, G. Repression of Astrocytic Connexins in Cortical and Subcortical Brain Regions and Prefrontal Enrichment of H3K9me3 in Depression and Suicide. Int. J. Neuropsychopharmacol. 2017, 20, 50–57. [Google Scholar] [CrossRef] [Green Version]
- Medina, A.; Watson, S.J.; Bunney, W., Jr.; Myers, R.M.; Schatzberg, A.; Barchas, J.; Akil, H.; Thompson, R.C. Evidence for alterations of the glial syncytial function in major depressive disorder. J. Psychiatr. Res. 2016, 72, 15–21. [Google Scholar] [CrossRef] [Green Version]
- Bernard, R.; Kerman, I.A.; Thompson, R.C.; Jones, E.G.; Bunney, W.E.; Barchas, J.D.; Schatzberg, A.F.; Myers, R.M.; Akil, H.; Watson, S.J. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol. Psychiatry 2011, 16, 634–646. [Google Scholar] [CrossRef]
- Torres-Platas, S.G.; Nagy, C.; Wakid, M.; Turecki, G.; Mechawar, N. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol. Psychiatry 2016, 21, 509–515. [Google Scholar] [CrossRef] [PubMed]
- Miguel-Hidalgo, J.J.; Moulana, M.; Deloach, P.H.; Rajkowska, G. Chronic Unpredictable Stress Reduces Immunostaining for Connexins 43 and 30 and Myelin Basic Protein in the Rat Prelimbic and Orbitofrontal Cortices. Chronic Stress (Thousand Oaks) 2018, 2, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kaut, O.; Sharma, A.; Schmitt, I.; Hurlemann, R.; Wüllner, U. DNA methylation of DLG4 and GJA-1 of human hippocampus and prefrontal cortex in major depression is unchanged in comparison to healthy individuals. J. Clin. Neurosci. 2017, 43, 261–263. [Google Scholar] [CrossRef] [PubMed]
- Xia, C.Y.; Wang, Z.Z.; Zhang, Z.; Chen, J.; Wang, Y.Y.; Lou, Y.X.; Gao, Y.; Luo, P.; Ren, Q.; Du, G.H.; et al. Corticosterone impairs gap junctions in the prefrontal cortical and hippocampal astrocytes via different mechanisms. Neuropharmacology 2018, 131, 20–30. [Google Scholar] [CrossRef]
- Sun, J.D.; Liu, Y.; Yuan, Y.H.; Li, J.; Chen, N.H. Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats. Neuropsychopharmacology 2012, 37, 1305–1320. [Google Scholar] [CrossRef] [Green Version]
- Huang, D.; Li, C.; Zhang, W.; Qin, J.; Jiang, W.; Hu, C. Dysfunction of astrocytic connexins 30 and 43 in the medial prefrontal cortex and hippocampus mediates depressive-like behaviours. Behav. Brain Res. 2019, 372, 111950. [Google Scholar] [CrossRef]
- Quesseveur, G.; Portal, B.; Basile, J.A.; Ezan, P.; Mathou, A.; Halley, H.; Leloup, C.; Fioramonti, X.; Deglon, N.; Giaume, C.; et al. Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice. Front. Cell. Neurosci. 2015, 9, 490. [Google Scholar] [CrossRef] [Green Version]
- Rajkowska, G.; Miguel-Hidalgo, J.J. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 2007, 6, 219–233. [Google Scholar] [CrossRef] [Green Version]
- Ren, Q.; Wang, Z.Z.; Chu, S.F.; Xia, C.Y.; Chen, N.H. Gap junction channels as potential targets for the treatment of major depressive disorder. Psychopharmacology 2018, 235, 1427–1437. [Google Scholar] [CrossRef]
- Dantzer, R. Cytokine, sickness behavior, and depression. Neurol. Clin. 2006, 24, 441–460. [Google Scholar] [CrossRef]
- Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E.K.; Lanctot, K.L. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010, 67, 446–457. [Google Scholar] [CrossRef] [PubMed]
- Lang, U.E.; Borgwardt, S. Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell. Physiol. Biochem. 2013, 31, 761–777. [Google Scholar] [CrossRef] [PubMed]
- Kim, Y.K.; Na, K.S.; Myint, A.M.; Leonard, B.E. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 277–284. [Google Scholar] [CrossRef] [PubMed]
- Araki, T.; Ikegaya, Y.; Koyama, R. The effects of microglia- and astrocyte-derived factors on neurogenesis in health and disease. Eur. J. Neurosci. 2021, 54, 5880–5901. [Google Scholar] [CrossRef] [PubMed]
- Cheslow, L.; Alvarez, J.I. Glial-endothelial crosstalk regulates blood-brain barrier function. Curr. Opin. Pharmacol. 2016, 26, 39–46. [Google Scholar] [CrossRef] [PubMed]
- Menard, C.; Pfau, M.L.; Hodes, G.E.; Kana, V.; Wang, V.X.; Bouchard, S.; Takahashi, A.; Flanigan, M.E.; Aleyasin, H.; LeClair, K.B.; et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 2017, 20, 1752–1760. [Google Scholar] [CrossRef] [Green Version]
- Rothhammer, V.; Quintana, F.J. Control of autoimmune CNS inflammation by astrocytes. Semin. Immunopathol. 2015, 37, 625–638. [Google Scholar] [CrossRef] [Green Version]
- De Bock, M.; Leybaert, L.; Giaume, C. Connexin Channels at the Glio-Vascular Interface: Gatekeepers of the Brain. Neurochem. Res. 2017, 42, 2519–2536. [Google Scholar] [CrossRef]
- Hodes, G.E.; Pfau, M.L.; Leboeuf, M.; Golden, S.A.; Christoffel, D.J.; Bregman, D.; Rebusi, N.; Heshmati, M.; Aleyasin, H.; Warren, B.L.; et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl. Acad. Sci. USA 2014, 111, 16136–16141. [Google Scholar] [CrossRef] [Green Version]
- McIntyre, R.S.; Filteau, M.J.; Martin, L.; Patry, S.; Carvalho, A.; Cha, D.S.; Barakat, M.; Miguelez, M. Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach. J. Affect. Disord. 2014, 156, 1–7. [Google Scholar] [CrossRef]
- Gaynes, B.N.; Lux, L.; Gartlehner, G.; Asher, G.; Forman-Hoffman, V.; Green, J.; Boland, E.; Weber, R.P.; Randolph, C.; Bann, C.; et al. Defining treatment-resistant depression. Depress. Anxiety 2020, 37, 134–145. [Google Scholar] [CrossRef] [PubMed]
- Minelli, A.; Zampieri, E.; Sacco, C.; Bazzanella, R.; Mezzetti, N.; Tessari, E.; Barlati, S.; Bortolomasi, M. Clinical efficacy of trauma-focused psychotherapies in treatment-resistant depression (TRD) in-patients: A randomized, controlled pilot-study. Psychiatry Res. 2019, 273, 567–574. [Google Scholar] [CrossRef] [PubMed]
- Koo, J.W.; Russo, S.J.; Ferguson, D.; Nestler, E.J.; Duman, R.S. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl. Acad. Sci. USA 2010, 107, 2669–2674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Widner, B.; Laich, A.; Sperner-Unterweger, B.; Ledochowski, M.; Fuchs, D. Neopterin production, tryptophan degradation, and mental depression--what is the link? Brain Behav. Immun. 2002, 16, 590–595. [Google Scholar] [CrossRef]
- Tilleux, S.; Hermans, E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J. Neurosci. Res. 2007, 85, 2059–2070. [Google Scholar] [CrossRef]
- Diniz, B.S.; Teixeira, A.L.; Talib, L.; Gattaz, W.F.; Forlenza, O.V. Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients. Am. J. Geriatr. Psychiatry 2010, 18, 172–176. [Google Scholar] [CrossRef]
- Yirmiya, R.; Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain. Behav. Immun. 2011, 25, 181–213. [Google Scholar] [CrossRef]
- Zunszain, P.A.; Anacker, C.; Cattaneo, A.; Choudhury, S.; Musaelyan, K.; Myint, A.M.; Thuret, S.; Price, J.; Pariante, C.M. Interleukin-1beta: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology 2012, 37, 939–949. [Google Scholar] [CrossRef] [Green Version]
- Pineda, E.A.; Hensler, J.G.; Sankar, R.; Shin, D.; Burke, T.F.; Mazarati, A.M. Interleukin-1β causes fluoxetine resistance in an animal model of epilepsy-associated depression. Neurotherapeutics 2012, 9, 477–485. [Google Scholar] [CrossRef] [Green Version]
- López-Muñoz, F.; Alamo, C. Monoaminergic neurotransmission: The history of the discovery of antidepressants from 1950s until today. Curr. Pharm. Des. 2009, 15, 1563–1586. [Google Scholar] [CrossRef]
- Xia, C.Y.; Chu, S.F.; Zhang, S.; Gao, Y.; Ren, Q.; Lou, Y.X.; Luo, P.; Tian, M.T.; Wang, Z.Q.; Du, G.H.; et al. Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes. J. Ethnopharmacol. 2017, 208, 207–213. [Google Scholar] [CrossRef] [PubMed]
- Morioka, N.; Nakamura, Y.; Zhang, F.F.; Hisaoka-Nakashima, K.; Nakata, Y. Role of Connexins in Chronic Pain and Their Potential as Therapeutic Targets for Next-Generation Analgesics. Biol. Pharm. Bull. 2019, 42, 857–866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jeanson, T.; Pondaven, A.; Ezan, P.; Mouthon, F.; Charveriat, M.; Giaume, C. Antidepressants Impact Connexin 43 Channel Functions in Astrocytes. Front. Cell. Neurosci. 2015, 9, 495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Valera, E.; Ubhi, K.; Mante, M.; Rockenstein, E.; Masliah, E. Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 2014, 62, 317–337. [Google Scholar] [CrossRef] [Green Version]
- Berk, M.; Williams, L.J.; Jacka, F.N.; O’Neil, A.; Pasco, J.A.; Moylan, S.; Allen, N.B.; Stuart, A.L.; Hayley, A.C.; Byrne, M.L.; et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013, 11, 200. [Google Scholar] [CrossRef] [Green Version]
- Kopra, E.; Mondelli, V.; Pariante, C.; Nikkheslat, N. Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review. J. Psychopharmacol. 2021, 35, 934–945. [Google Scholar] [CrossRef]
- Dominguini, D.; Steckert, A.V.; Michels, M.; Spies, M.B.; Ritter, C.; Barichello, T.; Thompson, J.; Dal-Pizzol, F. The effects of anaesthetics and sedatives on brain inflammation. Neurosci. Biobehav. Rev. 2021, 127, 504–513. [Google Scholar] [CrossRef]
- Yadavalli, C.; Garlapati, P.K.; Raghavan, A.K. Gallic Acid from Terminalia Bellirica Fruit Exerts Antidepressant-like Activity. Rev. Bras. De Farmacogn. 2020, 30, 357–366. [Google Scholar] [CrossRef]
- Jiang, N.; Lv, J.; Wang, H.; Huang, H.; Wang, Q.; Lu, C.; Zeng, G.; Liu, X.M. Ginsenoside Rg1 ameliorates chronic social defeat stress-induced depressive-like behaviors and hippocampal neuroinflammation. Life Sci. 2020, 252, 117669. [Google Scholar] [CrossRef]
- Wang, H.; Yang, Y.; Yang, S.; Ren, S.; Feng, J.; Liu, Y.; Chen, H.; Chen, N. Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression. Front. Pharmacol. 2021, 12, 709019. [Google Scholar] [CrossRef]
- Leonard, B.E. Inflammation and depression: A causal or coincidental link to the pathophysiology? Acta Neuropsychiatr. 2018, 30, 1–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Novakova, I.; Subileau, E.A.; Toegel, S.; Gruber, D.; Lachmann, B.; Urban, E.; Chesne, C.; Noe, C.R.; Neuhaus, W. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models. PLoS ONE 2014, 9, e86806. [Google Scholar] [CrossRef] [PubMed]
- Mesripour, A.; Shahnooshi, S.; Hajhashemi, V. Celecoxib, ibuprofen, and indomethacin alleviate depression-like behavior induced by interferon-alfa in mice. J. Complement. Integr. Med. 2019, 17, 6982. [Google Scholar] [CrossRef] [PubMed]
- Shan, B.Z.; Guo, B.; Li, Y.S.; Sun, X.F. Effect of celecoxib on protein expression of FAK and Cx43 in DMBA induced rat tongue carcinoma cells. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 9454–9463. [Google Scholar] [CrossRef]
- Prabhakaran, J.; Molotkov, A.; Mintz, A.; Mann, J.J. Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme. Molecules 2021, 26, 3208. [Google Scholar] [CrossRef]
- Froger, N.; Orellana, J.A.; Cohen-Salmon, M.; Ezan, P.; Amigou, E.; Saez, J.C.; Giaume, C. Cannabinoids prevent the opposite regulation of astroglial connexin43 hemichannels and gap junction channels induced by pro-inflammatory treatments. J. Neurochem. 2009, 111, 1383–1397. [Google Scholar] [CrossRef]
- Orellana, J.A.; Moraga-Amaro, R.; Diaz-Galarce, R.; Rojas, S.; Maturana, C.J.; Stehberg, J.; Saez, J.C. Restraint stress increases hemichannel activity in hippocampal glial cells and neurons. Front. Cell. Neurosci. 2015, 9, 102. [Google Scholar] [CrossRef] [Green Version]
- Bennett, M.V.; Garre, J.M.; Orellana, J.A.; Bukauskas, F.F.; Nedergaard, M.; Saez, J.C. Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res. 2012, 1487, 3–15. [Google Scholar] [CrossRef] [Green Version]
- O’Carroll, S.J.; Becker, D.L.; Davidson, J.O.; Gunn, A.J.; Nicholson, L.F.; Green, C.R. The use of connexin-based therapeutic approaches to target inflammatory diseases. Methods Mol. Biol. 2013, 1037, 519–546. [Google Scholar] [CrossRef]
- Buckner, C.M.; Luers, A.J.; Calderon, T.M.; Eugenin, E.A.; Berman, J.W. Neuroimmunity and the blood-brain barrier: Molecular regulation of leukocyte transmigration and viral entry into the nervous system with a focus on neuroAIDS. J. Neuroimmune Pharmacol. 2006, 1, 160–181. [Google Scholar] [CrossRef]
- Wang, G.; Wang, J.; Xin, C.; Xiao, J.; Liang, J.; Wu, X. Inflammatory response in epilepsy is mediated by glial cell gap junction pathway (Review). Mol. Med. Rep. 2021, 24, 493. [Google Scholar] [CrossRef] [PubMed]
- Garg, S.; Md Syed, M.; Kielian, T. Staphylococcus aureus-derived peptidoglycan induces Cx43 expression and functional gap junction intercellular communication in microglia. J. Neurochem. 2005, 95, 475–483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sera, T.; Komine, S.; Arai, M.; Sunaga, Y.; Yokota, H.; Kudo, S. Three-dimensional model of intracellular and intercellular Ca(2+) waves propagation in endothelial cells. Biochem. Biophys. Res. Commun. 2018, 505, 781–786. [Google Scholar] [CrossRef] [PubMed]
- Orellana, J.A.; Figueroa, X.F.; Sánchez, H.A.; Contreras-Duarte, S.; Velarde, V.; Sáez, J.C. Hemichannels in the neurovascular unit and white matter under normal and inflamed conditions. CNS Neurol. Disord. Drug Targets 2011, 10, 404–414. [Google Scholar] [CrossRef]
- Orellana, J.A.; Saez, P.J.; Shoji, K.F.; Schalper, K.A.; Palacios-Prado, N.; Velarde, V.; Giaume, C.; Bennett, M.V.; Saez, J.C. Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration. Antioxid. Redox Signal. 2009, 11, 369–399. [Google Scholar] [CrossRef]
- Hansson, E. Actin filament reorganization in astrocyte networks is a key functional step in neuroinflammation resulting in persistent pain: Novel findings on network restoration. Neurochem. Res. 2015, 40, 372–379. [Google Scholar] [CrossRef]
- Iyyathurai, J.; D’Hondt, C.; Wang, N.; De Bock, M.; Himpens, B.; Retamal, M.A.; Stehberg, J.; Leybaert, L.; Bultynck, G. Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: Gap junctions versus hemichannels. Neuropharmacology 2013, 75, 491–505. [Google Scholar] [CrossRef]
- De Bock, M.; Decrock, E.; Wang, N.; Bol, M.; Vinken, M.; Bultynck, G.; Leybaert, L. The dual face of connexin-based astroglial Ca(2+) communication: A key player in brain physiology and a prime target in pathology. Biochim. Biophys. Acta 2014, 1843, 2211–2232. [Google Scholar] [CrossRef] [Green Version]
- Panattoni, G.; Amoriello, R.; Memo, C.; Thalhammer, A.; Ballerini, C.; Ballerini, L. Diverse inflammatory threats modulate astrocytes Ca(2+) signaling via connexin43 hemichannels in organotypic spinal slices. Mol. Brain 2021, 14, 159. [Google Scholar] [CrossRef]
- Yang, F.; Zhao, K.; Zhang, X.; Zhang, J.; Xu, B. ATP Induces Disruption of Tight Junction Proteins via IL-1 Beta-Dependent MMP-9 Activation of Human Blood-Brain Barrier In Vitro. Neural Plast. 2016, 2016, 8928530. [Google Scholar] [CrossRef]
- Choi, A.J.; Ryter, S.W. Inflammasomes: Molecular regulation and implications for metabolic and cognitive diseases. Mol. Cells 2014, 37, 441–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Narcisse, L.; Scemes, E.; Zhao, Y.; Lee, S.C.; Brosnan, C.F. The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia 2005, 49, 245–258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saez, J.C.; Contreras-Duarte, S.; Gomez, G.I.; Labra, V.C.; Santibanez, C.A.; Gajardo-Gomez, R.; Avendano, B.C.; Diaz, E.F.; Montero, T.D.; Velarde, V.; et al. Connexin 43 Hemichannel Activity Promoted by Pro-Inflammatory Cytokines and High Glucose Alters Endothelial Cell Function. Front. Immunol. 2018, 9, 1899. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Y.T.; Wang, X.L.; Feng, S.T.; Chen, N.H.; Wang, Z.Z.; Zhang, Y. Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression. Pharmacol. Res. 2021, 171, 105761. [Google Scholar] [CrossRef] [PubMed]
- Sanacora, G.; Banasr, M. From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders. Biol. Psychiatry 2013, 73, 1172–1179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rouach, N.; Giaume, C. Connexins and gap junctional communication in astrocytes are targets for neuroglial interaction. Prog. Brain Res. 2001, 132, 203–214. [Google Scholar] [CrossRef]
- Ma, D.; Feng, L.; Cheng, Y.; Xin, M.; You, J.; Yin, X.; Hao, Y.; Cui, L.; Feng, J. Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia. J. Neuroinflamm. 2018, 15, 198. [Google Scholar] [CrossRef] [Green Version]
- Pitsillou, E.; Bresnehan, S.M.; Kagarakis, E.A.; Wijoyo, S.J.; Liang, J.; Hung, A.; Karagiannis, T.C. The cellular and molecular basis of major depressive disorder: Towards a unified model for understanding clinical depression. Mol. Biol. Rep. 2020, 47, 753–770. [Google Scholar] [CrossRef]
- Seifert, G.; Carmignoto, G.; Steinhauser, C. Astrocyte dysfunction in epilepsy. Brain Res. Rev. 2010, 63, 212–221. [Google Scholar] [CrossRef]
- Diaz, E.F.; Labra, V.C.; Alvear, T.F.; Mellado, L.A.; Inostroza, C.A.; Oyarzun, J.E.; Salgado, N.; Quintanilla, R.A.; Orellana, J.A. Connexin 43 hemichannels and pannexin-1 channels contribute to the alpha-synuclein-induced dysfunction and death of astrocytes. Glia 2019, 67, 1598–1619. [Google Scholar] [CrossRef]
Disease Types | Expression | Function | Pro-Inflammatory Cytokines | Anti-Inflammatory Cytokines | References |
---|---|---|---|---|---|
AD | Increase (Around Aβ) | Inhibition (GJCs) Promotion (HCs) | ↑ | ↓ | [29,30,31] |
PD | Increase (In rodent striatum) | — — | ↑ | ↓ | [28] |
MDD | Decrease | Inhibition (GJCs) Promotion (HCs) | ↑ | ↑ | [6] |
Epilepsy | Increase (In hippocampus) | Inhibition (GJCs) Promotion (HCs) | ↑ | ↓ | [28,32,33,34] |
Glioma | Increase (In the peri-tumor region) | Inhibition (GJCs) No significant increase (HCs) | ↑ | ↓ | [35,36,37] |
Ischemic Stroke | No significant change | Inhibition (GJCs) Promotion (HCs) | ↑ | ↓ | [38,39] |
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Jiang, H.; Zhang, Y.; Wang, Z.-Z.; Chen, N.-H. Connexin 43: An Interface Connecting Neuroinflammation to Depression. Molecules 2023, 28, 1820. https://doi.org/10.3390/molecules28041820
Jiang H, Zhang Y, Wang Z-Z, Chen N-H. Connexin 43: An Interface Connecting Neuroinflammation to Depression. Molecules. 2023; 28(4):1820. https://doi.org/10.3390/molecules28041820
Chicago/Turabian StyleJiang, Hong, Yi Zhang, Zhen-Zhen Wang, and Nai-Hong Chen. 2023. "Connexin 43: An Interface Connecting Neuroinflammation to Depression" Molecules 28, no. 4: 1820. https://doi.org/10.3390/molecules28041820
APA StyleJiang, H., Zhang, Y., Wang, Z. -Z., & Chen, N. -H. (2023). Connexin 43: An Interface Connecting Neuroinflammation to Depression. Molecules, 28(4), 1820. https://doi.org/10.3390/molecules28041820