Role of 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

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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 and is encoded by the TAC1 (3). In promote the corneal epithelial wound healing. Re- humans, the major mammalian TAC 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, (NKA), , 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 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 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. NK1R-T does not interact with b-arrestin, volves b-arrestin–associated internalization of SP-NK1R com- resulting in the impairment of SP-induced desensitization and plex in an endosome (Fig. 1B). The endosomal acidification endocytosis of the SP-NK1R complex (26). The NK1R-T is dissociates SP from the NK1R complex followed by degrada- found on human monocytes, macrophages, colonic epithelial tion of SP by endothelin-converting enzyme-1, a membrane cells of the colitis patients, and in the peripheral tissues, in- metalloendopeptidase (8). The degradation of SP frees NK1R cluding heart, lung, prostate, and spleen (19, 30). Furthermore, to recycle back to the cell surface (Fig. 1B). Recycling of NK1R NK1R-T has 10-fold lower affinity to SP than full-length is also regulated by the concentration of SP. After stimulation NK1R (20, 31). The intracellular signaling pathways for with a low concentration of SP (,1 nM), NK1R is minimally NK1R and NK1R-T are different; for example, SP stimulation phosphorylated and gets internalized into endosomes, but of NK1R-T did not activate NF-kBandshowedreduced rapidly dissociates from b-arrestin to recycle back to the cell mRNA expression of IL-8 (32, 33). NK1R-T stimulation in surface (24). However, a high concentration of SP (.10 nM) HEK 293 cells causes ERK1/2 phosphorylation, but the effects causes extensive NK1R phosphorylation, its internalization are seen after 15 min of incubation with SP (20, 32). In into endosomes, and prolonged association with b-arrestin contrast, full-length NK1R stimulation results in a rapid acti- (23). After prolonged stimulation with SP, the NK1R gets vation of ERK (within 1–2 min). NK1R-T stimulation in- ubiquitinated and traffics to lysosomes, where it gets degraded creases CCL5-induced intracellular calcium level in monocytes/ (Fig. 1B) (25). macrophages (19). These results demonstrate a cross-talk be- SP binding to NK1R also activates phospholipase C, which tween NK1R-T and CCR5, while interacting with their re- causes the formation of inositol triphosphate and diacylglycerol. spective ligands. However, more detailed studies are needed to Inositol triphosphate increases the level of cytosolic Ca2+, address the factors involved in upregulating NK1RT in chronic The Journal of Immunology 1545 inflamed tissues, and whether an increased level of NK1RT has schistosomiasis (48–50). Eosinophil activation by SP causes 2 beneficial or detrimental effects in resolving the inflammation their degranulation and release of O2 (51). This effect of SP and promoting the tissue repair. is mediated via its N terminus and was thought to be a receptor- independent event. However, more recently, eosinophils isolated SP and NK1R expression in immune cell types from atopic dermatitis patients were shown to express the higher Nerves containing SP are reported to innervate primary levels of NK2R, but not NK1R, at mRNA and protein levels (52). SP stimulation of eosinophils showed an increased influx of (thymus and bone marrow) and secondary lymphoid organs 2+ (spleen, lymph nodes, tonsils, and lymphoid aggregates in the Ca and inhibited their spontaneous apoptosis in cultures (52). gut) (34–36). This suggests that SP may act as a mediator of SP was also shown to have a chemotactic effect on eosinophils cross talk between the nervous and immune systems. In ad- derived from atopic dermatitis patients (52), suggesting that dition to their production from neurons, SP and its receptor eosinophils may propagate the itch cycle in atopic conditions NK1R are well documented to be expressed in different im- via SP. mune cell types. The expression of SP and its effect on im- Neutrophils. Neutrophils expressing SP are found in granulo- mune cells are summarized in Table I. Brief descriptions of mas and inflamed bronchoalveolar lavage (53, 54). SP stim- the role of SP in regulating the function of different immune ulation of human neutrophils causes superoxide production cell types follow. (55). This biological activity of SP is NK1R dependent and Mast cells. Mast cells are shown in close proximity to SP-positive involves an increased level of intracellular Ca2+ (56). SP also nerves in many tissues, including lung, intestine, dura matter, enhances the phagocytic activity of neutrophils and regulates Downloaded from diaphragm, and skin, suggesting the involvement of mast cells the influx of neutrophils in inflamed tissues (57). The influx in neurogenic inflammation (37–39). Earlier studies showed of neutrophils in inflamed tissue is NK1R mediated. A re- that SP can induce the release by mast cell duced influx of neutrophils and MPO activity was reported in degranulation, and this SP-mediated activity was considered the pancreas and lung tissue of NK1R-deficient mice in an to be the outcome of direct G protein–mediated activation acute pancreatitis mouse model (58). Similarly, IL-1b–induced rather than an NKR-mediated process (40, 41). However, neutrophil accumulation in a murine air-pouch model was http://www.jimmunol.org/ 2 2 later studies in both rat and human cultured mast cells impaired in NK1R / mice (59). SP administration in the showed the expression of the high-affinity SP receptor NK1R skin has been shown to cause the neutrophil accumulation in (42, 43), whereas the human intestinal mast cells (mucosal the skin tissue of mice, and the effect is dependent on skin- type) do not respond to SP, because they do not express any resident mast cells (60, 61). However, in vitro SP stimulation of the three NKRs under the homeostatic condition (44). of primary mouse neutrophils, purified from the peripheral Together, these studies suggest that SP exerts its function in blood by density gradient centrifugation, showed an increased an NK1R-independent and -dependent fashion on mast cells. expression of CCL3, CXCL2 chemokines and CCR1, CXCR2

In addition, studies show a bidirectional signal between mast chemokine receptors (62). These effects were NK1R dependent. by guest on September 24, 2021 cells and SP-expressing nerves. SP released from sensory neurons Together, these studies suggest a direct and indirect effect of SP acts on mast cells to produce TNF-a and vascular endothelial in regulating neutrophil function and influx in inflamed tissues. growth factor (45, 46). In contrast, mast cells can release the Monocytes/macrophages. Monocytes/macrophages in both human tryptase enzyme, which activates protease-activated receptor-2 and rodents are reported to express SP and its receptor NK1R on neurons and mediates the release of SP to induce neurogenic (63–65). In human mononuclear phagocytes, NK1R antagonist inflammation (47). treatment downregulates SP mRNA expression (66). While Eosinophils. SP is shown to present in human eosinophils (48). determining which form of NK1R is expressed, primary Similarly, immunostaining of SP is noted in eosinophils de- human monocytes and the undifferentiated human monocyte rived from liver granulomas of mice infected with murine cell line THP-1 were reported to express only NK1R-T (19, 67).

Table I. Expression and effects of SP in immune cell types

Immune Cell NK1R-Mediated Types SP Expression Effect SP or NK1R Signaling on Immune Cells References DCs Shown in human and Shown in human Potentiate immunostimulatory function and survival of DCs, IL- (75–79) mouse and mouse 12 production and generation of type I immunity. Monocytes/ Shown in human and Shown in human NK1R-T stimulation in monocytes augments CCR5 signaling and (67–70) macrophages mouse and mouse promotes M-tropic HIV infection. NK1R signaling enhances IL- 12 production in macrophages. Eosinophils Shown in human and Data not shown SP effects are NK2R mediated. Inhibit spontaneous apoptosis of (51, 52) mouse cells in culture, exerts chemotactic effect and causes the release of 2 O2 . Neutrophils Shown in human and Shown in human Causes superoxide production, enhances phagocytosis, increases (55, 57, 58, 62) mouse and mouse expression of chemokine and chemokine receptor. Mast cells Data not shown Shown in human Causes mast cell degranulation, TNF-a and vascular endothelial (40, 41, 45, 46) and mouse growth factor secretion. NK cells Shown in human and Shown in human Increases IFN-g production, either inhibits or enhances NK cell (81, 83–86) mouse and mouse cytotoxicity under defined set of condition. T lymphocytes Shown in human and Shown in human Enhances IL-2 and IFN-g production, promotes (89, 90, 92, 94) mouse and mouse proliferation, generation of memory Th17 from non-committed memory CD4 T cells. 1546 BRIEF REVIEWS: IMMUNOBIOLOGY OF SUBSTANCE P

The NK1R-T–expressing THP-1 cells, when stimulated with NK1R-T, and a preincubation with SP inhibits the NK cell’s SP, did not trigger Ca2+ response, but SP stimulation contact-dependent cytotoxicity. The inhibitory effect of SP was augmented CCL5-induced intracellular levels of Ca2+ in evident in the NK cell line (YTS), as well as in NK cells undifferentiated THP-1 cells, as well as in primary human purified from the human blood of healthy volunteers (84). In monocytes (67). These studies suggest a critical interaction this study, preincubation with SP did not affect NF-kB between NK1R-T and CCR5 in augmenting CCL5-induced activation, but inhibited the prolonged increase in Ca2+ level effects in monocytes. In fact, the NK1R antagonists have in NK cells after its interaction with the target cell. SP been shown to inhibit HIV infection of macrophages, preincubation also inhibited activation receptor–induced suggesting the importance of SP via NK1R-T in enhancing phosphorylation of ERK in NK cells. However, in the absence M-tropic HIV infection (68, 69). In mice, SP induces p35 of preincubation and the use of different concentrations, SP has and p40 mRNA in cultured macrophages via NK1R, and been shown to stimulate the cytotoxicity of NK cells (85, 86). LPS stimulation further augments the secretion of bioactive Thus, under a defined set of conditions, SP can inhibit the IL-12p70 (70). Moreover, IL-12 induces SP (PPTA) expression cytotoxicity of NK cells. in splenic macrophages, suggesting that IL-12 and SP regulate T lymphocytes. Resting T cells do not express SP and its receptor, each other’s expression in murine macrophages (71). In addition but activated human T lymphocytes are shown to express the to IL-12, IL-23 has also been reported to regulate SP levels in PPTA gene and produce SP neuropeptide (87). Similarly, in mouse macrophages, which is subject to inhibition by TGF-b rodents, activated T cells express NK1R, and SP released from cytokine (72). SP exerts its action on mouse macrophages activated T cells may act in an autocrine fashion to regulate Downloaded from through high-affinity NK1R, and it causes NF-kB activation T cell proliferation (75). It is reported that IL-12 augments, 2+ without increasing the intracellular Ca levels (29, 73). NK1R whereas IL-10 blocks, the SP production from murine T cells expression in mouse peritoneal macrophages is upregulated (72). IL-12 also induces SP receptor NK1R in murine T cells by Th1 (IFN-g)andTh2(IL-4)cytokines(74).Together, (88). SP has also been shown to enhance IL-2 expression in these reports provide convincingevidencefortheexpression activated human T cells and promote T cell proliferation (89, and function of SP in both human and rodent monocytes/ 90). In human T lymphocytes, SP is reported to enhance the http://www.jimmunol.org/ macrophages. expression of MIP-1b, suggesting that SP action on T cells Dendritic cells. Dendritic cells (DCs) play an important role for may promote the chemotaxis of CCR5 (MIP-1b receptor)- the generation of an adaptive T cell response to non-self- expressing immune cells (91). Recently, in the presence of antigens. SP and its receptors NK1R and NK2R are present monocytes, SP-NK1R interaction has been shown to promote in both mouse and human DCs (75, 76). In mice, bone the generation of human memory Th17 cells from non-Th17 marrow–derived DCs (BMDCs) were shown to express the committed memory CD4 T cells (92). In murine schistosomiasis g-transcript of the PPTA gene and produce SP at protein parasitic infection, granuloma eosinophils produce SP, and CD4

levels as determined by immunostaining (75). BMDCs T cells isolated from the granulomas are shown to express by guest on September 24, 2021 expressing SP potentiate allogeneic T cell proliferation NK1R, suggesting that SP-NK1R interaction in granulomas through NK1R (75). In addition, BMDCs stimulated with may involve CD4 T cells (93). In fact, SP is reported to NK1R agonist produce IL-12, which when injected in vivo enhance schistosome egg Ag-induced IFN-g production in induces type I immunity (77). Similarly, in vivo administra- NK1R-expressing T cells from schistosome-infected mice (94). tion of NK1R agonist has been shown to potentiate the Together, these studies show the functional role of SP on immunostimulatory functions of skin-resident Langerhans activated, but not naive, T cells. cells to induce an Ag-specific type I immunity in a mouse model (78). NK1R signaling of BMDCs has also been shown Role of SP in regulating immune response to microbial infection to promote the survival of DCs (79), suggesting a possible in Multiple studies have documented the role of SP in viral, vivo role of SP in maintaining tissue-resident DC populations bacterial, and parasitic infection (95–97). The known roles of under the homeostatic condition, especially in tissues highly SP in regulating the immunity to viral, bacterial, and parasitic innervated with sensory nerves such as the skin and cornea. infections are summarized in the following subsections. NK cells. NK cells are granular lymphocytes, which are SP and its receptor in viral infections. Among viral infections, the primarily involved in controlling viral load in inflamed role of SP is well reported in murine g herpes virus 68 (HV- tissues by targeting virus-infected cells. Human NK cells are 68) infection. HV-68 is a g-2 herpes virus that infects the reported to express functional NK1R, and a dose-dependent epithelial cells and establishes the latency in immune cell types effect of SP on NK cell migration was seen in vitro with or such as B cells, macrophages, and DCs (98, 99). HV-68 without IL-2 stimulation (80). SP-NK1R interaction has also infection of C57BL/6 (B6) mice is shown to cause an increased been shown to promote IFN-g production from murine NK mRNA expression of PPTA and SP receptor in the spleen and cells in a bacterial infection model (81). In contrast, the role of mesenteric lymph node of infected mice (100). In the same study, SP in inhibiting the cytotoxicity of NK cells is well described in NK-1R–deficient mice exhibited reduced CTL response and an studies related with HIV-seropositive subjects. In patients with increased level of latent virus. Similarly, mice genetically deficient HIV infection, higher amounts of SP are seen in human for the PPTA gene, after HV-68 infection, were shown to have plasma, and it correlates with lower number and depressed an ∼100-fold higher viral load in the lungs in comparison with function of NK cells (82). The ex vivo experiments carried control B6 mice (101). This was associated with an increased out on PBMCs isolated from HIV-seropositive subjects lung pathology and an increased level of latent virus in the showed that SP antagonist CP-96345 increases the cytolytic spleens of PPTA-deficient mice. Together, these studies suggest activity of NK cells (83). A detailed study further showed that, in the absence of SP or its receptor, the host immunity to that human NK cells express both full-length NK1R and HV-68 infection is significantly compromised. The Journal of Immunology 1547

The role of SP has also been investigated in detail in HIV relevant bacterial CNS pathogens, Neisseria meningitides and infection. An increased level of SP is reported in the blood Borrelia burgdorferi. After exposure to either of these two plasma of HIV-infected men and women (82, 102). In ad- pathogens, SP was shown to augment proinflammatory dition, HIV infection of cultured macrophages causes an in- cytokine production in the isolated cultures of CNS-resident creased expression of SP (103). In contrast, in vitro addition microglia and astrocyte cell types (118). Moreover, NK1R- of SP has been shown to enhance the replication of HIV in deficient mice demonstrated a decreased level of inflammatory blood-isolated mononuclear phagocytes (104, 105). This ef- cytokines after CNS infection of these pathogens (118). fect of SP is mediated via NK1R-T. The latter enhances HIV SP and its receptor in parasitic infections. The role of SP in parasitic entry into immune cells via CCR5, because the use of non- infection is also well documented. It is reported that SP is involved peptide SP antagonist (CP-96,345) inhibits HIV infection of in regulating the size of granuloma formation postinfection with macrophages and downregulates CCR5 (68). In compari- larval cysts of the cestode taenia solium. Mice deficient in SP son with CP-96,345, NK1R antagonist is more precursor or NK1R showed much smaller granulomas and a lesser potent ex vivo to suppress the HIV infection of myeloid-derived level of IL-6, TNF-a,andIL-1b proteinincomparisonwithwild- macrophages (69). Aprepitant treatment has also been shown to type infected mice (119). Mice can get infected with Schistosoma reduce viral load in SIV-infected macaques and reduce the mansoni, which colonize the human intestine, and thus mice are proinflammatory cytokines in HIV-positive individuals, sug- considered a good model to study schistosomiasis. Schistosome gesting that the NK1R antagonist might be of use as an adjunct eggs in liver induced chronic granulomatous inflammation, and therapy in HIV infection (106). SP expression in granulomas was shown to control the levels of Downloaded from SP is also reported to play an important role during infection inflammatory cytokines (120). NK1R knockout mice in response with paramyxoviruses. Sendai virus is an ssRNA virus of to schistosome infection develop smaller granulomas and show the Paramyxoviridae family. Sendai virus infection of the reduced levels of IFN-g and IgG2a (120, 121). SP involvement Guinea pig increases the expression of SP in the cell body of the hasalsobeenshowninamurinemodelofTrypanosoma brucei afferent neurons in nodose ganglia (107). The inducible ex- infection, because the infected mice treated with SP antagonist pression of SP suggests its involvement in virus-induced air- RP67,580 developed reduced neuroinflammation (122). http://www.jimmunol.org/ way inflammation. In fact, NK1R antagonist treatment of However, Trypanosoma infection of NK1R knockout mice Guinea pigs, infected with Sendai virus, was shown to limit showed more severe neuroinflammation than wild-type virus-induced bronchoconstriction (108). Similarly, in a rat mice (123). Interestingly, treatment with NK2 and NK3 model of respiratory syncytial virus (RSV) infection, an in- antagonist reduced neuroinflammation in the knockout mice, creased expression of SP receptor was noted after lung infection suggesting that in the absence of NK1R signaling SP can still with RSV (109). Challenge of RSV-infected rats with capsaicin exert its function through weaker affinity receptors NK2R and resulted in airway inflammation, and NK1R antagonist treat- NK3R. In fact, NK1R has been shown to act as a negative

ment abrogated the effect of capsaicin (110). feedback for basal and activity-induced release of SP from by guest on September 24, 2021 Similar to HIV, the spread of measles virus (MV) from one neurons, and an increased level of SP is noted in the skin of 2 2 cell to another is partly dependent on SP receptor NK1R. The NK1R / mice (124). fusion protein of MV shares the C-terminal sequence of SP, and pharmacological inhibition of the NK1R is shown to Role of SP in ocular inflammation reduce the spreading of MV (111, 112). Neurkinin-1 receptor Multiple reports have shown the role of SP in ocular in- signaling is also reported to regulate innate immune defense flammation (125). Human samples obtained from the pa- to genital herpes virus infection (113). NK1R-deficient mice tients with pterygium showed the expression of SP and NK1R exhibited an enhanced level of HSV-2 in the genital tract, in pterygium fibroblasts. Moreover, the cell culture studies which was associated with an impaired NK cell cytotoxicity in show that SP via NK1R induces the migration of pterygium the vaginal tissue. This study suggested that lack of NK1R fibroblast and microvascular endothelial cells, suggesting that signaling compromises innate immunity to HSV-2 infection. SP may contribute to the pathogenesis of Pterygia through its NK1R signaling is also reported to regulate corneal HSV-1 profibrogenic and angiogenic action (126). In allergic con- infection–induced inflammation, as described later in the Role junctivitis patients, a higher level of SP was found in the tear of SP in ocular inflammation section. fluid (127). The treatment of conjunctivitis in patients with SP and its receptor in bacterial infections. The best studied role of ocular allergy and in an animal model is reported to reduce SP in augmenting the immunity to bacterial infection was the SP level in tears (128–130). Subconjunctival injections of shown in a mouse model of Salmonella infection. The suc- SP are also shown to cause conjunctivitis and increase the cessful clearance of Salmonella infection requires IL-12–in- permeability of conjunctival blood vessels (129). Recently, duced production of IFN-g, and the latter enhances macrophage SP-NK1R interaction is reported to cause the loss of anterior and DC activation to eliminate the Salmonella infection (114). chamber–associated immune deviation after retinal laser Oral infection with Salmonella causes a rapid and dramatic burns in a rodent model (131). The study showed that retinal upregulation of SP and NK1R mRNA in mucosal tissues (115, laser burns in one eye resulted in an increase in NK1R ex- 116). Mice pretreated with spantide II, NK1R antagonist, before pression in the retina of both eyes, and the local use of NK1R oral challenge with Salmonella became highly susceptible to antagonists prevented the bilateral loss of anterior chamber– bacterial infection, because spantide II treatment reduced associated immune deviation. SP has also been shown to cause IL-12p40 mRNA expression and impeded the bacterial clearance the rejection of second corneal allograft transplant (132). Using (116). In a murine model of pneumococcal meningitis, therapeutic a mouse model of penetrating keratoplasty, it was shown that targeting of NK1R was shown to limit neuroinflammation (117). severing the corneal nerves during surgery released SP in both Another proinflammatory role of SP was described in two clinically eyes, which disabled CD4+CD25+ regulatory T cells (Tregs) 1548 BRIEF REVIEWS: IMMUNOBIOLOGY OF SUBSTANCE P that were required for allograft survival (132). Although the corneal opacity and angiogenesis (145). In addition to HSK, underlying mechanism by which SP abolished the immuno- SP is also reported to regulate the severity of bacterial keratitis suppressive activity of Tregs is not clear, the study showed the in induced in response to corneal Pseudomonas aeruginosa in- vivo ability of SP to regulate Treg function in an animal model. fection in resistant BALB/c and susceptible B6 mouse model SP has also been shown to stimulate the corneal neo- (81, 148). In these studies, SP was shown to adversely affect vascularization through NK1R (133). The possible underlying the disease by elevating the levels of proinflammatory cyto- mechanism could be the direct action of SP on vascular en- kines and the growth factors in infected corneas (149). The dothelial cells, because functional NK1R is known to express use of SP antagonist spantide I was shown to reduce type I on HUVECs, and the growth-promoting effects of SP on and enhanced type II cytokine in the infected cornea of B6 vascular endothelial cells are reported in serum-free cul- mice, leading to an improved disease outcome (150). SP was ture condition (134, 135). SP may also indirectly promote also reported to delay the apoptosis of polymorphonuclear hemangiogenesis in tissues by recruiting granulocytes with cells, and blocking SP interaction with NK1R promotes an angiogenic potential from the blood circulation (136). Under earlier apoptosis and improves disease outcome in susceptible these conditions, SP can perform its chemotactic activity or B6 mice (151). Together, these studies show the involvement cause mast cell degranulation to recruit the granulocytes in of SP in promoting infection-induced corneal inflammation. inflamed tissue (137). In addition to the development of new blood vessels, SP via NK1R is known to promote the vaso- Role of SP in corneal wound healing dilation of existing blood vessels, resulting in plasma extrav- In addition to its role in microbial inflammation, SP is Downloaded from asation (138, 139). Recently, SP has been shown to regulate reported to play an important role in corneal wound healing. lymphangiogenesis in an animal model of diet-induced obe- SP is present in corneal nerves, normal tears, and is also sity (140). The study showed that NK1R antagonist treat- expressed in the corneal epithelium and stromal keratocytes ment reduced abnormal lymphangiogenesis in visceral adipose (152–156). Although normal cornea has resident immune cell tissue of allergen-sensitized obese mice. SP is also known to populations such as macrophages and DCs, they are not effectively modulate the contractility of lymphatic vessels via reported to express SP in the corneal tissue. Among SP re- http://www.jimmunol.org/ its direct effect on lymphatic muscle cells (141). The direct ceptors, NK1R is expressed in corneal epithelial and kerato- effect of SP is mediated via NK1R and NK3R molecules, cytes (155, 156). SP via NK1R increases the half-life of IL-8 which are expressed on lymphatic muscle cells and are in- transcripts in human corneal epithelial cells, resulting in the volved in the activation of p38MAPK and ERK1/2 molecules enhancement of IL-8 synthesis (154). Similarly, the primary (142). The development of hemangiogenesis and lym- human keratocytes expressing the full-length form of NK1R phangiogenesis in avascular cornea is likely to affect the visual upon SP stimulation secrete increased levels of chemotactic acuity by causing edema and the influx of immune cells in IL-8 protein, which contributes significantly to SP-enhanced corneal tissue (143). Recently, in two different models of keratocyte migration (155). Together, these events suggest by guest on September 24, 2021 corneal angiogenesis (alkali burn and sutures), topical appli- that SP-NK1R interaction promotes corneal wound healing. cation of NK1R antagonist is shown to effectively In fact, SP is reported to promote diabetic corneal epithelial reduce both hemangiogenesis and lymphangiogenesis in the wound healing via NK1R (157). In an alkali-burn model of inflamed cornea (144). Moreover, treatment with the NK1R mouse and rabbit eyes, SP was shown to mobilize CD29+ antagonist is shown to inhibit corneal (hem and stromal cells from the bone marrow into the circulation, and lymph) angiogenesis after this has been established in an an- subsequently to the injured tissue to accelerate the process of imal model. wound healing (158). The process of corneal epithelial wound SP has also been reported to regulate virus- and bacteria- healing involves migration of corneal epithelial cells over the induced inflammation in the cornea. In a mouse model of denuded surface followed by their proliferation to increase the corneal HSV-1 infection, SP has been shown to regulate the normal thickness of the epithelium (159). Unlike in a diabetic severity of herpes stromal keratitis (HSK) induced in response mouse model, topical application of SP treatment alone is not to corneal HSV-1 infection (145). In this study, intense SP effective to promote injury induced corneal epithelial wound staining was noted in the posterior stroma of the eyes with healing in a rabbit model (160). However, SP is known to act severe HSK, whereas the eyes with mild HSK showed SP synergistically with insulin-like growth factor-1 (IGF-1) to staining on the apical surface of the corneal epithelium. The promote corneal epithelial cell migration and their attachment intense SP staining noted in the corneal stroma could be the to extracellular matrix proteins in ex vivo cultures (161). The outcome of SP expression by stromal keratocytes/fibroblasts, combined effect of SP/IGF-1 was concentration dependent of diffusion of SP from aqueous humor, and SP secreted from each factor and was mediated by NK-1R, but not by NK2R the sympathetic nerves. A recent study has shown hyperin- and NK3R (162). The signaling events associated with the nervation of the corneal stroma of HSK developing in eyes combined treatment involve protein kinase C activation, p38 with sympathetic nerves that are originating from superior MAPK activation, and upregulation of a5 integrin (163– cervical ganglion (146). The cultured explants of superior 165). The latter is expressed on actively migrating corneal cervical ganglion are reported to increase the level of SP in epithelial cells. In rabbits, the administration of eye drops response to stimulation with IL-1b cytokine (147). In HSV- containing both SP and IGF-1 was shown to promote corneal 1–infected corneas, NK1R expression was seen in both epithelial wound healing (166). SP/IGF-1 treatment was also 2 CD45 and CD45+ cells, suggesting that SP is likely exerting reported to improve the barrier function and enhance epithelial its action on both immune and nonimmune cells. Moreover, wound healing in animal models of neurotrophic keratopathy, a subconjunctival injection of NK1R antagonist spantide I, persistent corneal epithelial defect condition that results from during the clinical phase of HSK, was shown to reduce the insults to the trigeminal nerve (167, 168). The Journal of Immunology 1549

In addition to full-length SP, the 4-aa sequence (FGLM- strategy to control SP-induced inflammatory events is heavily amide) derived from the C-terminal end of SP along with dependent upon blocking its high-affinity receptor NK1R via IGF-1 effectively stimulates the corneal epithelial cell migra- peptide or nonpeptide NK1R antagonists. However, this strategy tion in a rabbit model of corneal wound healing (169). SP- does not take into account the interaction of available SP in derived peptide and IGF-1 have also been shown to promote inflamed tissue with lesser affinity SP receptor NK2R/NK3R and corneal epithelial wound healing in diabetic rats (170). Sim- its outcome on ongoing tissue inflammation. Future experimental ilarly, a tetrapeptide (SSSR) derived from the C-domain of and clinical studies should look into strategies to further increase IGF-1 acts synergistically with FGLM-amide to promote the efficacy of the treatments targeting SP-induced inflammation. corneal epithelial wound healing (171). Shortening of SP and At the same time, one should not overlook the beneficial effects IGF-1 retained their synergistic effect but prevented their of SP, especially on wound healing or in homeostasis of the undesirable side effects, such as SP-induced miosis (172) and corneal epithelium. IGF-1–induced angiogenesis (173). These encouraging ob- servations resulted in the clinical trials to treat persistent Disclosures corneal epithelial defects with topical application of SP or SP- The authors have no financial conflicts of interest. derived peptide along with IGF-1 molecule. Eye drops con- taining FGLM-amide and IGF-1 were shown to treat a pa- References tient with neurotrophic keratopathy (174). The treatment 1. v. Euler, U. S., and J. H. Gaddum. 1931. An unidentified depressor substance in resulted in reduced corneal opacity and the closure of the cor- certain tissue extracts. J. Physiol. 72: 74–87. Downloaded from neal epithelial defect. Similarly, eye drops containing FGLM- 2. Chang, M. M., S. E. Leeman, and H. D. Niall. 1971. Amino-acid sequence of substance P. Nat. New Biol. 232: 86–87. amide and SSSR were shown to induce a rapid 3. Pennefather, J. N., A. Lecci, M. L. Candenas, E. Patak, F. M. Pinto, and resurfacing of the corneal epithelium in individuals with C. A. Maggi. 2004. Tachykinins and tachykinin receptors: a growing family. Life Sci. 74: 1445–1463. neurotrophic keratopathy (175). Together, these studies show 4. Krause, J. E., J. M. Chirgwin, M. S. Carter, Z. S. Xu, and A. D. Hershey. 1987. the beneficial effect of SP in association with IGF-1 to induce Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc. Natl. Acad. Sci. USA 84: 881–885. corneal epithelial wound healing under experimental and 5. Nawa, H., T. Hirose, H. Takashima, S. Inayama, and S. Nakanishi. 1983. Nu- http://www.jimmunol.org/ clinical conditions. cleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature 306: 32–36. 6. Bonner, T. I., H. U. Affolter, A. C. Young, and W. S. Young, III. 1987. A cDNA Role of SP in corneal epithelial homeostasis encoding the precursor of the rat neuropeptide, . Brain Res. 388: 243–249. The cornea is highly innervated with sensory nerves that 7. Zhang, Y., L. Lu, C. Furlonger, G. E. Wu, and C. J. Paige. 2000. Hemokinin is a produce neuropeptides such as SP and gene-related hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat. Immunol. 1: 392–397. peptide (cGRP) (176). 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Substance inflammation, suggesting SP may have a physiological role in p-fibronectin-cytokine interactions in myeloproliferative disorders with bone maintaining the corneal epithelium homeostasis (153, 179). marrow fibrosis. Acta Haematol. 109: 1–10. 14. Corbally, N., D. Powell, and K. F. Tipton. 1990. The binding of endogenous and In fact, SP has recently been shown to inhibit hyperosmotic exogenous substance-P in human plasma. Biochem. Pharmacol. 39: 1161–1166. stress-induced apoptosis of the corneal epithelial cells in ex 15. Maggi, C. A., R. Patacchini, P. Rovero, and A. Giachetti. 1993. Tachykinin re- vivo cultures (180). SP-NK1R interaction is also reported to ceptors and antagonists. J. Auton. Pharmacol. 13: 23–93. 16. Gerard, N. P., L. Bao, H. Xiao-Ping, and C. Gerard. 1993. Molecular aspects of regulate the expression of E-cadherin and ZO-1 tight junction the tachykinin receptors. Regul. Pept. 43: 21–35. proteins in the corneal epithelial cells, and thereby demon- 17. 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The role 1550 BRIEF REVIEWS: IMMUNOBIOLOGY OF SUBSTANCE P

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