Substance P—Friend or Foe
- (1)
- SP is involved in transmitting pain impulses [3]. However, although SP is one of the predominant neuropeptide that is involved in transmitting pain impulses, there are several other neuropeptides that transmit pain impulses, such as vasoactive intestinal peptide [4], calcitonin gene-related peptide [5], and cholecystokinin [6].
- (2)
- SP has various effects on immune cells [7] as follows: SP enhances the survival and immunostimulatory capacity of dendritic cells [8,9,10,11,12]. SP enhances IL-12 production in macrophages [7,13]. SP inhibits spontaneous apoptosis while causing chemotaxis of eosinophils [7,14,15]. SP induces superoxide production, phagocytosis, and chemotaxis of neutrophils [7,16,17,18]. SP induces mast cell degranulation and modulates NK cell cytotoxicity [7]. SP promotes proliferation of activated T-cells and induces generation of memory TH17 cells [19,20,21]. However, SP is not indispensable; there are several other mediators that induce the above effects on immune cells.
- (3)
- There are few and sparse reports that SP plays a beneficial role in microbial infections, for example the absence of SP leads to the host immunity to murine gamma herpes virus 68 (HV-68) and genital herpes virus (HSV-2) infection being significantly compromised [22,23]. In addition, SP has been shown to augment immunity to Salmonella in a murine model [24]. However, there are contrasting derogatory roles of SP in other important microbial infections that is outlined below.
- (4)
- SP has shown to be protective following acute ischemia-reperfusion. For example, in acute ischemia reperfusion studies, SP has been shown to provide important vasodilatory effects that presumably appear to be protective initially by increasing myocardial reperfusion. However, there are contrasting derogatory roles of SP in the cardiovascular setting that is outlined below.
1. Derogatory Role of SP
2. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Euler, U.S.v.; Gaddum, J.H. An unidentified depressor substance in certain tissue extracts. J. Physiol. 1931, 72, 74–87. [Google Scholar] [CrossRef]
- Chang, M.M.; Leeman, S.E.; Niall, H.D. Amino-acid sequence of substance P. Nat. New Biol. 1971, 232, 86–87. [Google Scholar] [CrossRef] [PubMed]
- Harrison, S.; Geppetti, P. Substance P. Int. J. Biochem. Cell Biol. 2001, 33, 555–576. [Google Scholar] [CrossRef]
- McDougall, J.J.; Watkins, L.; Li, Z. Vasoactive intestinal peptide (VIP) is a of joint pain in a rat model of osteoarthritis. Pain 2006, 123, 98–105. [Google Scholar] [CrossRef] [PubMed]
- Schou, W.S.; Ashina, S.; Amin, F.M.; Goadsby, P.J.; Ashina, M. Calcitonin gene-related peptide and pain: A systematic review. J. Headache Pain 2017, 18, 34. [Google Scholar] [CrossRef] [Green Version]
- Rowlingson, J.C.M. Cholecystokinin and Its Antagonists in Pain Management. Anesth. Analg. 2007, 104, 750. [Google Scholar] [CrossRef]
- Munoz, M.; Covenas, R. Involvement of substance P and the NK-1 receptor in human pathology. Amino Acids 2014, 46, 1727–1750. [Google Scholar] [CrossRef]
- Lambrecht, B.N.; Germonpre, P.R.; Everaert, E.G.; Carro-Muino, I.; De Veerman, M.; de Felipe, C.; Hunt, S.P.; Thielemans, K.; Joos, G.F.; Pauwels, R.A. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur. J. Immunol. 1999, 29, 3815–3825. [Google Scholar] [CrossRef]
- Marriott, I.; Bost, K.L. Expression of authentic substance P receptors in murine and human dendritic cells. J. Neuroimmunol. 2001, 114, 131–141. [Google Scholar] [CrossRef]
- Janelsins, B.M.; Sumpter, T.L.; Tkacheva, O.A.; Rojas-Canales, D.M.; Erdos, G.; Mathers, A.R.; Shufesky, W.J.; Storkus, W.J.; Falo, L.D.; Morelli, A.E., Jr.; et al. Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12. Blood 2013, 121, 2923–2933. [Google Scholar] [CrossRef] [Green Version]
- Mathers, A.R.; Tckacheva, O.A.; Janelsins, B.M.; Shufesky, W.J.; Morelli, A.E.; Larregina, A.T. In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1- and Tc1-biased immune responses. J. Immunol. 2007, 178, 7006–7017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janelsins, B.M.; Mathers, A.R.; Tkacheva, O.A.; Erdos, G.; Shufesky, W.J.; Morelli, A.E.; Larregina, A.T. Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity. Blood 2009, 113, 3017–3026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kincy-Cain, T.; Bost, K.L. Substance P-induced IL-12 production by murine macrophages. J. Immunol. 1997, 158, 2334–2339. [Google Scholar] [PubMed]
- Kroegel, C.; Giembycz, M.A.; Barnes, P.J. Characterization of eosinophil cell activation by peptides. Differential effects of substance P, melittin, and FMET-Leu-Phe. J. Immunol. 1990, 145, 2581–2587. [Google Scholar] [PubMed]
- Raap, M.; Rudrich, U.; Stander, S.; Gehring, M.; Kapp, A.; Raap, U. Substance P activates human eosinophils. Exp. Dermatol. 2015, 24, 557–559. [Google Scholar] [CrossRef] [Green Version]
- Serra, M.C.; Bazzoni, F.; Della Bianca, V.; Greskowiak, M.; Rossi, F. Activation of human neutrophils by substance P. Effect on oxidative metabolism, exocytosis, cytosolic Ca2+ concentration and inositol phosphate formation. J. Immunol. 1988, 141, 2118–2124. [Google Scholar]
- Bar-Shavit, Z.; Goldman, R.; Stabinsky, Y.; Gottlieb, P.; Fridkin, M.; Teichberg, V.I.; Blumberg, S. Enhancement of phagocytosis—A newly found activity of substance P residing in its N-terminal tetrapeptide sequence. Biochem. Biophys. Res. Commun. 1980, 94, 1445–1451. [Google Scholar] [CrossRef]
- Sun, J.; Ramnath, R.D.; Bhatia, M. Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils. Am. J. Physiol. Cell Physiol. 2007, 293, C696–C704. [Google Scholar] [CrossRef]
- Payan, D.G.; Brewster, D.R.; Goetzl, E.J. Specific stimulation of human T lymphocytes by substance P. J. Immunol. 1983, 131, 1613–1615. [Google Scholar]
- Cunin, P.; Caillon, A.; Corvaisier, M.; Garo, E.; Scotet, M.; Blanchard, S.; Delneste, Y.; Jeannin, P. The tachykinins substance P and hemokinin-1 favor the generation of human memory Th17 cells by inducing IL-1beta, IL-23, and TNF-like 1A expression by monocytes. J. Immunol. 2011, 186, 4175–4182. [Google Scholar] [CrossRef] [Green Version]
- Suvas, S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis. J. Immunol. 2017, 199, 1543–1552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Payne, C.M.; Heggie, C.J.; Brownstein, D.G.; Stewart, J.P.; Quinn, J.P. Role of tachykinins in the host response to murine gammaherpesvirus infection. J. Virol. 2001, 75, 10467–10471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Svensson, A.; Kaim, J.; Mallard, C.; Olsson, A.; Brodin, E.; Hokfelt, T.; Eriksson, K. Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection. J. Immunol. 2005, 175, 6802–6811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kincy-Cain, T.; Bost, K.L. Increased susceptibility of mice to Salmonella infection following in vivo treatment with the substance P antagonist, spantide II. J. Immunol. 1996, 157, 255–264. [Google Scholar] [PubMed]
- Li, Y.; Sun, Y.; Liu, B.; Sun, Y.; Chen, P.; Xie, K.; Wang, Y.; Zhu, J. Prolonged administration of aprepitant improves cisplatin-based chemotherapy-induced nausea and vomiting. Future Oncol. 2022, 18, 2533–2543. [Google Scholar] [CrossRef] [PubMed]
- Munoz, M.; Covenas, R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 2013, 48, 1–9. [Google Scholar] [CrossRef]
- Munoz, M.; Covenas, R.; Esteban, F.; Redondo, M. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J. Biosci. 2015, 40, 441–463. [Google Scholar] [CrossRef]
- Munoz, M.; Covenas, R. The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer? Cancers 2020, 12, 2682. [Google Scholar] [CrossRef]
- Munoz, M.; Rosso, M.; Covenas, R. Neurokinin-1 Receptor Antagonists against Hepatoblastoma. Cancers 2019, 11, 1258. [Google Scholar] [CrossRef] [Green Version]
- Munoz, M.; Covenas, R. The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia. J. Clin. Med. 2020, 9, 1659. [Google Scholar] [CrossRef]
- Ho, W.Z.; Douglas, S.D. Substance P and neurokinin-1 receptor modulation of HIV. J. Neuroimmunol. 2004, 157, 48–55. [Google Scholar] [CrossRef] [PubMed]
- Ho, W.Z.; Cnaan, A.; Li, Y.H.; Zhao, H.; Lee, H.R.; Song, L.; Douglas, S.D. Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res. Hum. Retrovir. 1996, 12, 195–198. [Google Scholar] [CrossRef] [PubMed]
- Barrett, J.S.; Spitsin, S.; Moorthy, G.; Barrett, K.; Baker, K.; Lackner, A.; Tulic, F.; Winters, A.; Evans, D.L.; Douglas, S.D. Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. J. Transl. Med. 2016, 14, 148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jacoby, D.B.; Yost, B.L.; Elwood, T.; Fryer, A.D. Effects of neurokinin receptor antagonists in virus-infected airways. Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 279, L59–L65. [Google Scholar] [CrossRef]
- Chauhan, V.S.; Kluttz, J.M.; Bost, K.L.; Marriott, I. Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of pneumococcal meningitis. J. Immunol. 2011, 186, 7255–7263. [Google Scholar] [CrossRef]
- Chauhan, V.S.; Sterka, D.G., Jr.; Gray, D.L.; Bost, K.L.; Marriott, I. Neurogenic exacerbation of microglial and astrocyte responses to Neisseria meningitidis and Borrelia burgdorferi. J. Immunol. 2008, 180, 8241–8249. [Google Scholar] [CrossRef] [Green Version]
- Legi, A.; Rodriguez, E.; Eckols, T.K.; Mistry, C.; Robinson, P. Substance P Antagonism Prevents Chemotherapy-Induced Cardiotoxicity. Cancers 2021, 13, 1732. [Google Scholar] [CrossRef]
- Choi, J.E.; Di Nardo, A. Skin neurogenic inflammation. Semin. Immunopathol. 2018, 40, 249–259. [Google Scholar] [CrossRef]
- Graefe, S.B.; Mohiuddin, S.S. Biochemistry, Substance P. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Weinstock, J.V. Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta Physiol. 2015, 213, 453–461. [Google Scholar] [CrossRef]
- Bhatia, M.; Saluja, A.K.; Hofbauer, B.; Frossard, J.L.; Lee, H.S.; Castagliuolo, I.; Wang, C.C.; Gerard, N.; Pothoulakis, C.; Steer, M.L. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc. Natl. Acad. Sci. USA 1998, 95, 4760–4765. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.F.; Ge, T.T.; Fan, J.; Yang, W.; Cui, R.J. The role of substance P in epilepsy and seizure disorders. Oncotarget 2017, 8, 78225–78233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Robinson, P.; Garza, A.; Weinstock, J.; Serpa, J.A.; Goodman, J.C.; Eckols, K.T.; Firozgary, B.; Tweardy, D.J. Substance P causes seizures in neurocysticercosis. PLoS Pathog. 2012, 8, e1002489. [Google Scholar] [CrossRef] [PubMed]
- Robinson, P.; Taffet, G.E.; Engineer, N.; Khumbatta, M.; Firozgary, B.; Reynolds, C.; Pham, T.; Bulsara, T.; Firozgary, G. Substance P receptor antagonism: A potential novel treatment option for viral-myocarditis. Biomed Res. Int. 2015, 2015, 645153. [Google Scholar] [CrossRef] [PubMed]
- Garza, A.; Lackner, A.; Aye, P.; D’Souza, M.; Martin, P., Jr.; Borda, J.; Tweardy, D.J.; Weinstock, J.; Griffiths, J.; Robinson, P. Substance P receptor antagonist reverses intestinal pathophysiological alterations occurring in a novel ex-vivo model of Cryptosporidium parvum infection of intestinal tissues derived from SIV-infected macaques. J. Med. Primatol. 2008, 37, 109–115. [Google Scholar] [CrossRef] [PubMed]
- Lisowska, B.; Lisowski, A.; Siewruk, K. Substance P and Chronic Pain in Patients with Chronic Inflammation of Connective Tissue. PLoS ONE 2015, 10, e0139206. [Google Scholar] [CrossRef]
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Robinson, P.; Rodriguez, E.; Muñoz, M. Substance P—Friend or Foe. J. Clin. Med. 2022, 11, 3609. https://doi.org/10.3390/jcm11133609
Robinson P, Rodriguez E, Muñoz M. Substance P—Friend or Foe. Journal of Clinical Medicine. 2022; 11(13):3609. https://doi.org/10.3390/jcm11133609
Chicago/Turabian StyleRobinson, Prema, Emma Rodriguez, and Miguel Muñoz. 2022. "Substance P—Friend or Foe" Journal of Clinical Medicine 11, no. 13: 3609. https://doi.org/10.3390/jcm11133609