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Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

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Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis This information is current as Susmit Suvas of September 24, 2021. J Immunol 2017; 199:1543-1552; ; doi: 10.4049/jimmunol.1601751 http://www.jimmunol.org/content/199/5/1543 Downloaded from References This article cites 182 articles, 67 of which you can access for free at: http://www.jimmunol.org/content/199/5/1543.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis Susmit Suvas Substance P (SP) is an undecapeptide present in the hypotensive and spasmogenic activity. Because the activity of CNS and the peripheral nervous system. SP released this factor resided in the water-soluble powdered extracts of the from the peripheral nerves exerts its biological and brain and intestinal tissue, it was initially named as “prepara- immunological activity via high-affinity neurokinin 1 tion P” and then later “Substance P.” In the early 1970s, Chang receptor (NK1R). SP is also produced by immune cells et al. (2) determined the amino acid composition of SP. SP is and acts as an autocrine or paracrine fashion to regulate comprised of 11 aa (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- the function of immune cells. In addition to its proin- Leu-Met-NH2) and has a net positive charge under physio- flammatory role, SP and its metabolites in combina- logical pH (2). SP is a member of the tachykinin (TAC) family Downloaded from tion with insulin-like growth factor-1 are shown to of neuropeptides and is encoded by the TAC1 gene (3). In promote the corneal epithelial wound healing. Re- humans, the major mammalian TAC genes are TAC1, TAC3, cently, we showed an altered ocular surface homeosta- and TAC4. The human TAC1 gene consists of seven exons and 2 2 encodes for SP, neurokinin A (NKA), neuropeptide K, and sis in unmanipulated NK1R / mice, suggesting the neuropeptide-g (4, 5). TAC1 encodes for preprotachykinin A role of SP-NK1R signaling in ocular surface homeosta- (PPTA) mRNA, whereas TAC3 and TAC4 encode for pre- http://www.jimmunol.org/ sis under steady-state. This review summarizes the protachykinin B and preprotachykinin C mRNA, respectively immunobiology of SP and its effect on immune cells (6, 7). PPTA mRNA undergoes alternative splicing to give rise and immunity to microbial infection. In addition, the to aPPTA, bPPTA, gPPTA, and dPPTA mRNA transcripts effect of SP in inflammation, wound healing, and cor- (Fig. 1A). Out of the four isoforms of PPTA mRNA, aPPTA neal epithelial homeostasis in the eye is discussed. and dPPTA give rise to SP peptide only, whereas bPPTA yields The Journal of Immunology, 2017, 199: 1543–1552. to SP and NKA peptide, and the gPPTA transcript encodes for SP, NKA, and neuropeptide-g (8). ubstance P (SP) is an 11-aa-long neuropeptide, which is SP is present in a large amount in the CNS and the peripheral by guest on September 24, 2021 produced by neuronal and nonneuronal cells, including nervous system (9). In neurons, SP is expressed in the soma. S the immune cells. SP is known to exert its biological Once synthesized, SP is transported in large dense-core vesicles activity through G protein–coupled neurokinin receptors (LDCVs) and the peptide is released through the exocytosis of (NKRs) named neurokinin 1 receptor (NK1R), NK2R, and LDCVs either at axonal terminals or at the neuronal soma NK3R. Among the three, NK1R has the highest affinity for SP. (Fig. 1B) (10). Once exocytosed, SP binds to membrane-bound SP-NK1R interaction is widely reported to regulate immune SP receptor expressed either on the same cell or on the neigh- cells’ function and the immunity to microbial infection. In boring cells. Unbound SP can be degraded by a cell surface addition, SP is also reported to promote ocular inflammation, metalloendopeptidase named neprilysin, and thereby suggests wound healing, and tissue homeostasis. The focus of this review a shorter half-life of SP in tissues (11, 12). However, SP can is 3-fold: 1) to provide an overview of the biology of SP; 2) to prolong its half-life by interacting with high m.w. factors such describe the effect of SP on immune cells and the immunity to as fibronectin (13). In support, SP is reported to be more stable microbial infection; and 3) to describe the role of SP in ocular in blood plasma (14). Thus, SP may form a complex with other inflammation, wound healing, and tissue homeostasis. molecules to prolong its half-life in tissue or in the blood. NKRs Discovery, chemical composition, and the biosynthesis of SP Biological activity of SP is mediated through NKRs. NKRs In 1931, v. Euler and Gaddum (1) discovered that the pow- belong to the class I (rhodopsin-like) family of G protein– dered extracts of the equine (horse) brain and intestine had coupled receptors (15, 16). There are three different types of Department of Ophthalmology/Kresge Eye Institute, Wayne State University School of Address correspondence and reprint requests to Dr. Susmit Suvas, Wayne State Univer- Medicine, Detroit, MI 48201; Department of Anatomy and Cell Biology, Wayne State sity School of Medicine, 7223 Scott Hall, 540 East Canfield Avenue, Detroit, MI 48201. University School of Medicine, Detroit, MI 48201; and Department of Immunology E-mail address: [email protected] and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201 Abbreviations used in this article: B6, C57BL/6; BMDC, bone marrow–derived DC; Received for publication October 12, 2016. Accepted for publication June 13, 2017. DC, dendritic cell; HSK, herpes stromal keratitis; HV-68, herpes virus 68; IGF-1, insulin-like growth factor-1; LDCV, large dense-core vesicle; NKA, neurokinin A; This work was supported by National Institutes of Health/National Eye Institute Grant NKR, neurokinin receptor; NK1R, neurokinin 1 receptor; NK1R-T, truncated NK1R; EY022417 (to S.S.), Research to Prevent Blindness (to the Department of Ophthalmology), PPTA, preprotachykinin A; RSV, respiratory syncytial virus; SP, substance P; TAC, and National Institutes of Health/National Eye Institute Core Grant for Vision Research tachykinin. EY004068 (to Dr. Linda D. Hazlett, Wayne State University School of Medicine). Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601751 1544 BRIEF REVIEWS: IMMUNOBIOLOGY OF SUBSTANCE P Downloaded from FIGURE 1. (A) Schematic of human TAC1 gene mRNA splice variants. The neuropeptide products are indicated by colored boxes on mRNA structures, and the number denotes the coding exon for each TAC derived from the various isoforms of PPTA. (B) Schematic representation of SP production by a neuronal cell and an immune cell type. The outcome of SP binding to a target cell expressing high-affinity SP receptor, NK1R, is depicted as NK1R-associated signaling events http://www.jimmunol.org/ along with an internalization of the SP-NK1R complex, and the recycling of free NK1R to the cell surface after degradation of SP in the endosomal complex. AC, adenylate cyclase; DAG, diacylglycerol; ECE-1, endothelin-converting enzyme-1; GRK, G-protein coupled receptor kinase; IP3, inositol triphosphate; MEKS, MAPK; PKC, protein kinase C; PLC, phospholipase C. NKRs: NK1R, NK2R, and NK3R. The affinity of these whereas diacylglycerol activates protein kinase C. NK1R sig- NKRs in binding to SP is in the order of NK1R . NK2R . naling can also activate adenylyl cyclase, which causes the NK3R (17). In humans, two naturally occurring isoforms of generation of cAMP, and the latter activates protein kinase A NK1R are found in neuronal and immune cell types (18–21). (Fig. 1B). In NK1R-transfected rat kidney epithelial cells, these by guest on September 24, 2021 They are named as full-length NK1R or NK1R and truncated signaling events cause an activation of ERK1/2, a member of NK1R (NK1R-T). NK1R is made up of 407 aa residues and MAPKs (26). The nuclear translocation of ERK1/2 is necessary has one C-terminal intracellular domain, whereas NK1R-T is for the proliferation and antiapoptotic effect of SP (26). NK1R 311 aa long, but lacks the 90-aa-long C-terminal intracellular signaling may also cause an activation of p38 MAPK and NF- domain (22). kB transcription factor (27, 28). In macrophages, SP-induced NK1R signaling involves phosphorylation of the C-terminal NF-kB activation requires ERK1/2 and p38 MAPK activa- domain of NK1R by G protein–coupled receptor kinases, tion, which results in the expression of MIP-2 and MCP-1 resulting in the interaction of NK1R with b-arrestin adapter chemokine (29). proteins. b-Arrestin plays a central role in desensitization of In contrast with NK1R, the signaling property of NK1R-T is cells to SP signaling (8, 23). The desensitization process in- less well studied.
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