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Review Article Substance P and Its Role in Viral Infection

Review Article Substance P and Its Role in Viral Infection

Int J Clin Exp Med 2018;11(12):12946-12955 www.ijcem.com /ISSN:1940-5901/IJCEM0072488

Review Article and its role in viral infection

Wenya Xu1*, Tongsong Wang2*, Hongwei Zhou1,3

1Department of Ophthalmology, Lianshui County People’s Hospital, Huai’an, China; 2Department of Pharmacy and Biomedical Sciences, De Duve Institute, Université Catholique de Louvain, Brussels, Belgium; 3School of Medi- cine, Southeast University, Nanjing, China. *Equal contributors. Received September 6, 2017; Accepted September 10, 2018; Epub December 15, 2018; Published December 30, 2018

Abstract: Substance P (SP) is an 11- of the tachykinin family that preferentially activates the neurokinin-1 (NK1R). Early studies identified a role for SP and the NK1R in the digestive system, re- spiratory system, urogenital system, skin, nervous system, immune system, and tumors. More recently, SP and the NK1R have gained attention for their role in multiple viral infections, such as human immunodeficiency virus (HIV), HSV (herpes simplex keratitis), encephalomyocarditis virus (EMCV), respiratory syncytical virus (RSV), measles virus (MV), Epstein-Barr virus (EBV), enterovirus 71 (EV71) and so on. However, to date no human clinical assays using NK-1 receptor antagonists against viral infections have been developed, expect HIV. The use of as anti- HIV therapy has been tested in human clinical trials, although this NK-1 showed no significant anti-viral activity. NK-1 receptor antagonists merit further investigation as potential therapeutic antiviral agents. In this review, we update the involvement of the SP/NK-1 receptor system in viral infections, with the aim of providing insights for future anti-viral chemotherapy studies.

Keywords: Substance P, NK1-R, aprepitant, viral infection

Introduction 1 (NK1-R), NK2-R and NK3-R, which are encod- ed by TACR1, TACR2, and TACR3, respectively. Substance P (SP) is an 11-amino acid Nk1-R has the strongest affinity for SP, and that belongs to the tachykinin family. Together NK1-R is commonly regarded as the SP recep- with its receptors, SP play roles in a variety of tor [6]. NK1-R has two isoforms: the full-length pathophysiological processes. This article receptor and the truncated receptor [7]. reviews the effects of SP and its receptors on viral infection. SP is mainly synthesized by neurons, while some studies have shown that immune cells SP, first detected in the horse brain and small also express SP mRNA during the process of intestine, promotes intestinal and simian immunodeficiency virus (SIV)/human acts as an anti-hypertensive agent. It is the first immunodeficiency virus (HIV) infection [8]. member of the brain-gut peptide family, which NK1-R is mainly expressed in T cells, B cells, is expressed in intestinal nerve cells, intestinal monocytes/macrophages, NK cells, endocrine cells and canial nerve cells [1]. In and neurons [9]. 1970, 0.15 mg of pure SP was isolated from bovine tissue [2] and deter- After SP activates NK1-R in the human embry- mined its amino acid sequence [3]. Later, bio- onic kidney 293 (HEK293) cell line, it causes logically functional human SP was synthesized rapid morphological changes, including the for- [4]. mation of cytoplasmic membrane vesicles [10], which are related to intracellular communica- TAC1 (tachykinin-1) has two isomers, ΑTAC1 tion [11]. The binding of SP to NK1-R succes- and ΒTAC1, which were initially cloned from the sively activates recep- bovine striatum [5]. Both mRNAs are translated tor (EGFR), mitogen-activated protein kinase into the SP protein. The tachykinin family com- (MAPK) and extracellular signal-regulated pro- prises 3 receptors, namely neurokinin receptor tein kinase (ERK), and thus induces DNA syn- Substance P and viral infection thesis and cell proliferation [12, 13]. This mech- fonic acid activates the transient receptor anism partially mediates the ability of SP to potential cation channel subfamily V member promote the healing of colon epithelial cells 1, also called vanilloid receptor 1, promotes SP [14]. Mucosal healing is related to the anti- release and causes neurogenic colon inflam- apoptotic effects of SP, and the related signal- mation [28]. NK1-R activation by ing pathways include Janus kinase 2 (JAK-2) microglia and the p38 MAPK signaling pathway and phosphatidylinositol 3-kinase (PI3K)-me- causes visceral [29]. The binding diated activation of the apoptotic molecule of SP to NK1-R promotes the secretion of protein kinase B (PKB) [15]. The binding of SP enzymes, , vasoactive intestinal to the NK1-R receptor in the U373MG cell line peptide (VIP) and M2 muscarinic receptors in activates p38 and then induces the production the mucous membrane of the respiratory tract of pro-inflammatory factors, including IL-6 and [30]. SP and NK1-R play roles in airway all- IL-8 [16]. SP also activates nuclear factor kap- ergic reactions [31]. SP causes bladder hyper- pa-light-chain-enhancer of activated B cells sensitivity by promoting intercellular adhesion (NF-кB) through Rho family kinases and protein molecule-1-mediated and reac- kinase C δ (PKCδ), resulting in the production of tive oxygen species production [32]. SP pro- IL-6, IL-8, and tumor necrosis factor-α (TNF-α) motes the exudation of plasma by blood ves- [17]. The binding of SP to NK1-R results in the sels, the degranulation of mast cells, the expression of cyclooxygenase-2 (COX-2) and generation of reactive oxygen species and the prostaglandin E2 [18]. SP activates a truncated expression of pro-inflammatory , che- NK1-R to inhibit IL-8 expression [19]. Treatments mokines, adhesion molecules and COX-2 in the that block NK1-R glycosylation promote NK1-R bladder. SP promotes male sperm motility and endocytosis and inhibit IL-8 secretion [20]. participates in erection [33]. SP induces the Dorsal root ganglion neurons release SP, which production of pro-inflammatory factors [34] mediates and and nerve growth factors in skin keratinocytes, [6]. SP mainly mediates pain through two sig- which regulates the regeneration of mucosal naling pathways, the Ca2+-phospholipid-depen- nerves [35]. SP promotes cutaneous nerve dent protein kinase pathway [21] and the axon regeneration and wound healing [36]. SP cAMP-dependent protein kinase pathway [22]. plays a role in pain conduction by increasing glutamate release [37]. Strategies that reduce The termination of SP signaling pathways relies SP expression in the mouse spinal cord relieve on the degradation of SP by the brain-endor- cancer-induced pain [38]. NK1-R antagonists phin enzyme [23]. In addition, G-protein cou- inhibit pain [39]. SP promotes the release of pled receptor kinase 2 (GRK2), GRK3, and cytokines, chemokines, matrix metalloprotein- GRK5 cause Nk1-R phosphorylation and fur- ases and reactive oxygen species from neutro- ther desensitization [24]. phils, thereby promoting their phagocytosis of bacteria [40]. SP promotes the aggregation of The main pathophysiological functions of sub- dendritic cells and regulates the response of stance P have been determined. SP and its the lung to inhaled antigens [41]. SP promotes receptors play roles in the digestive system, the growth of a variety of cancers, whereas , urogenital system, skin, NK1-R antagonists inhibit the growth of many nervous system, immune system, and tumors. cancer cells [42]. Stimulation of the intestinal nerves leads to NK1-R endocytosis in the intestinal muscle SP plays roles in the pathological processes of layer, which is associated with nerve conduc- multiple viral infections and has both anti-viral tion, SP release and NK1-R activation [25]. SP and pro-viral effects. The application of its activates the non-selective channel in receptor antagonist as a treatment for viral the interstitial cells of Cajal, controlling the infections has yielded promising preliminary intestinal excitatory rhythm [26]. The expres- results. The antiviral mechanisms of host pro- sion of SP and NK1-R in the mucosal surface is teins do not rely on viral DNA polymerase, which increased by micro-cryptosporidium infection reduces the likelihood of viral drug resistance, in the jejunum of rhesus monkeys, leading to and some host proteins penetrate the blood- the release of chloride ions and the inhibition of brain barrier and the blood-ocular barrier. absorption [27]. Three-nitrophenyl sul- Therefore, we have reviewed the relevant stud-

12947 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection ies, with the aim of providing insights for future tion efficiency in cells expressing CD163, and anti-viral chemotherapy studies. the efficiency of HIV infection is decreased in CD163 knockout macrophages. The binding of The role of substance P and its receptor in HIV SP to NK1-R increases the intracellular calcium infection concentrations in mononuclear cells and the differentiation of monocytes to macrophages; The role of SP in HIV infection moreover, macrophages expressing high levels of CD163 on the cell membrane are more sen- receptor agonists inhibit glycopro- sitive to HIV infection [45]. SP promotes HIV tein 120 (Gp120)-mediated extracellular calci- infection in fetal brain cells that express full- um influx; significantly reduce the permeability length NK1-R receptors; the intracellular calci- of human microvascular endothelial cells; um concentration increases in cultured fetal inhibit zonula occludens-1 (ZO-1), claudin-5, brain cells after SP addition. The NK1-R recep- and adhesion molecule-1 expression; inhibit tor antagonist aprepitant prevents these ef- human monocyte extravasation through the fects, whereas the addition of SP to the cul- blood-brain barrier; and reduce the blood-brain tured HIV-1-infected fetal brain cells increases barrier permeability. HIV-1 infection changes HIV-1 expression. Cocktail therapy does not the structure and function of the blood-brain remove HIV-1 from the , barrier, which may be related to HIV-related but aprepitant provides protection through the dementia. The mechanism may be mediated by blood-brain barrier. NF-κB expression increas- the activation of brain endothelial cells by es after SP binds to the full-length NK1-R, Gp120 and other viral components, leading to which promotes the expression of HIV/SIV in the increased blood-brain barrier permeability. lymphocytes and monocytes and activates the Gp120 functions through an SP-mediated path- latent HIV in hematopoietic progenitors [46]. way to alter the expression of tight junction pro- teins and the permeability of cerebral endothe- Treatments that block NK1-R receptors inhibit lial cells. In addition, Gp120 directly promotes HIV infection SP secretion, thus playing a role in HIV-related dementia. SP and Gp120 directly reduce the Selective (5-hydroxy-trytamine) re- expression of ZO-1 and claudin-5 proteins, uptake inhibitors and SP antagonists increase resulting in increased blood-brain barrier per- the innate immunity of NK cells infected with meability [43]. SIV-infected apes have been HIV. Meanwhile, the function of NK cells is sig- used as a non-human primate model to study nificantly enhanced, which play a key role in AIDS neuropathy. The expression levels of SP inhibiting HIV infection. The plasma SP levels and NK1-R are increased in SIV encephalitis. are elevated in HIV-infected patients. SP direct- Macrophages are the main cells expressing ly increases HIV replication in macrophages NK1-R, and all SIV-infected macrophages ex- and T cells or indirectly increases HIV replica- press NK1-R. SP-treated macrophages express tion by altering beta-chemokine and receptor C-C chemokine receptor type 5 (CCR5) and expression. Based on the results of in vitro NK1-R on the cell membrane. An SP pretreat- experiments, the SP antagonist CP-96345 sig- ment increases SP and CCR5-mediated che- nificantly increases the activity of NK cells in mical chemotaxis, revealing the crosstalk the peripheral blood of HIV-infected women between NK1-R and CCR5. SP promotes cellu- [47]. Morphine withdrawal increases HIV infec- lar transport through the blood-brain barrier, tivity in T lymphocytes by inducing SP expres- thereby accelerating the development of SIV sion. Sudden withdrawal and progressive with- encephalitis. According to a pathology study, drawal of morphine promotes HIV replication in NK1-R was expressed in the cingulate gyrus of human T cells with latent infections, and its patients who died of HIV encephalitis, which is mechanism is related to the increased ex- similar to the results of SIV encephalitis [44]. pression of SP in peripheral blood lymphocytes The ability of HIV to infect macrophages is and T cells. drugs significantly increase strengthened in the presence of cluster of dif- HIV infectivity. The SP receptor antagonist ferentiation 163 (CD163), and SP also increas- CP-96345 not only blocks morphine withdrawal es HIV infection of macrophages by inducing caused by endogenous SP expression but also CD163 expression. HIV displays greater infec- eliminates withdrawal-induced HIV replication

12948 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection in T cells [48]. The SP receptor antagonist apre- the percentage of substance P-immunoreactive pitant prevents HIV-1 infection and exerts a neurons by two thirds. Treatment with bone synergistic effect in combination with other morphogenetic protein 7 (BMP-7) reversed the antiretroviral drugs. NK1-R receptor antago- LAT-induced increase in SP expression in cul- nists effectively penetrate the blood-brain bar- tured cells, but the BMP-7 treatment did not rier and thus play important roles in modulating affect the survival of the cultured neurons. LAT the inflammatory response in the brain. In HIV- expression did not affect SP expression in the 1-infected cultured peripheral blood mononu- neurons in the dorsal root of the spinal cord. In clear cells, the HIV-1 activity was determined by the mouse HSK model, the SP level was higher measuring the expression of the p24 antigen, in the corneas of mice with severe symptoms and the joint application of aprepitant with rito- than in the corneas of mice with mild symp- navir or saquinavir exerted synergistic effects. toms, and SP was mainly expressed in the cor- HIV-1 must be transmitted by CCR5, C-X-C motif neal stroma and co-localized with β-III tubulin+ chemokine receptor 4 (CXCR4) or both; the and IAb+ type cells. Based on these results, the non-peptide SP receptor antagonists CP-96345 SP content was 15-fold higher in the corneas of and aprepitant decrease CCR5 expression mice with severe symptoms than in the corneas (CCR5 is the main HIV-1 receptor in macro- of mice with mild symptoms. Corneas express- phages) to further inhibit HIV infection of mac- ing high levels of SP also contained higher lev- rophages [49]. Phase 1 clinical trials of aprepi- els of pro-inflammatory factors and chemical tant as a treatment for HIV-1 infection was chemokines, and subconjunctival injection of performed and the results showed that the the SP receptor antagonist spantide II signifi- number of CD4+ T cells expressing programmed cantly reduced the corneal opacity and neovas- death 1 (PD-1) and the concentrations of SP cularization in the clinical stage of the mouse and soluble CD163 were decreased in the plas- HSK model. In addition, the severity of HSK ma of HIV-infected patients treated with aprepi- lesions and the clearance rate of corneal virus tant [50]. In this clinical trial, the dosage of were irrelevant. Although different virus clear- aprepitant was 375 mg/day for 2 weeks, and ance rates may lead to different severity of cor- the results showed that the drug was safe and neal symptoms, the corneal swabs collected at had a significant biological effect, although an various time points failed to show a statistically obvious anti-viral effect was not observed. significant difference in the amount of the virus Vapreotide is a synthetic analog of somatosta- present in the corneas between mice with mild tin that exerts effects by blocking the symptoms and mice with severe symptoms. NK1-R receptors, and it inhibits the SP-induced HSV-1 replication in the cornea is required increase in intracellular calcium concentra- to cause inflammation in the corneal stroma; tions, NF-κB activation, and IL-8 and MCP-1 however, the presence of the virus is not neces- generation. In vitro, vapreotide inhibits HIV sary to cause persistent lesions in the corneal infection of human macrophages derived from tissue. SP regulates the inflammatory response mononuclear cells; these effects disappeared to HSK in mice with differing degrees of symp- when cells were pretreated with SP [51]. tom severity, but there were no statistically significant differences in the corneal levels of SP plays a role in the pathological process of the virus in mice with different inflammatory herpes virus infection responses [54].

The corneal sensitivity and SP levels decreased The effect of SP on herpes virus infection is rapidly in a mouse model of herpes simplex controversial keratitis (HSK), and the SP level recovered later than corneal sensitivity. SP does not partici- SP increased NO production in macrophages pate in the disappearance of the blink reflex in infected with HSV-1, but the effect decreas- the cornea, and SP could play an unknown role ed or disappeared after 24 hours [55]. SP in the cornea [52]. Hamza Ma and his team increased the formation of HSV-1 plaques in a [53] transformed primary cultured rat embry- time dependent in macrophages treated with onic trigeminal ganglion cells with plasmids SP after HSV infection, and the effect was encoding HSV-1 latency-associated transcript most evident 10 hours after SP treatment. (LAT) and the results showed that LAT increased However, pretreatment with SP before HSV-1

12949 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection infection had no effect on the formation of characterized by cardiac inflammation and car- HSV-1 plaques, but promoted the secretion diomyocyte necrosis. Murine myocarditis ca- of inflammatory factors in HSV-1-infected used by infection with encephalomyocarditis macrophages. virus (EMCV) is a commonly used experimental model to study viral myocarditis. SP was As shown in the study by Svensson and his required for the pathological process of EMCV team, the level of the SP expression was signifi- infection in mice, and 8-week-old wild-type cantly increased in the vagina of HSV-2-infected C57BL/6 mice infected with EMCV exhibited a mice. Furthermore, lack of SP signaling through 61-fold increase in SP levels [59]. EMCV- the use of mice deficient in NK1R, revealed an induced death, heart enlargement, heart in- important role for SP in the innate defense flammation, necrosis, apoptosis and hyperpla- against HSV-2 [56]. The amount of HSV-2 virus sia were not observed in SP knockout mice. in the genital tract of NK1-R-deficient mice The SP expression level and the density of SP infected with HSV-2 was significantly increased, immunopositive cells decreased in the hearts and the progression of the disease was signifi- of 4-week-old DBA/2 mice on the 6th day cantly accelerated, which was associated with after EMCV infection [60]. SP levels in the an impaired NK cell activity in the genital tract. hearts and ratio of heart weight to body weight However, NK1-R deficiency had no effect on the of the mice was negatively correlated at 6 days, animals’ ability to mount a protective immune indicating that the level of SP in the heart is response to HSV-2 following vaccination with related to the severity of viral myocarditis and an attenuated virus. In conclusion, the present heart function. The plasma SP level was also results indicated that, the SP-NK1-R signaling lower on the 6th day and had decreased further pathway plays a role in innate immunity against by the 14th day after infection. The authors HSV-2 in mice. The average cytotoxicity of each postulated that the reduced SP level may be NK cell in the vagina of NK1-R-/- mice decreased related to the destruction of nerve fibers in the 8-fold, which impaired their ability to control heart that contain SP. Because SP is distribut- viral replication. SP and NK1-R receptor block- ed throughout the heart conduction system, ers did not affect the ability of HSV-1 to form the decrease in SP levels may affect cardiac plaques, but 10-5 M SP reduced the plaque electrical conduction and cause arrhythmia. formation capacity by 42% [57]. Another However, in the above mentioned study by research found that tachykinin 1 (TAC1) or Robinson P and his team, the SP level increased TACR1 -deficient mice are more suscepti- in 8-week-old mice on the 14th day after EMCV ble to the respiratory pathogen murine gamma infection, but myocardial necrosis and inflam- herpes virus (MHV-68), but mice lacking both mation did not occur in SP knockout mice [59]. the TAC1 and NK1-R (NK1-/-xTAC1-/-) are The differences between the two previous stud- more resistant to MHV-68 [58]. This may be ies may be related to the different types and due to a lack of feedback inhibition of other ages of mice used. The binding of SP to its SP-binding receptors in these mouse. The receptor activates Rho A, leading to hypertro- study reconfirmed the roles of the TAC1 and phy and apoptosis in cultured cardiomyocytes TACR1 genes in controlling viral infections, but in vitro [61]. manifested the complexity of the mechanism of the peptide-receptor interactions. Deletion SP receptor antagonists protect against viral of the TAC1 gene and consequent lack of both myocarditis SP and NKA leads to an increased susceptibili- ty to MHV-68 infection, which may because of Pretreatment and posttreatment 1.2 mg/kg decreased inflammatory and specific cytotoxic with aprepitant significantly reduced mortality, T cell responses. heart size, cardiomyocyte size and viral RNA content in mice infected with 50 PFU of EMCV The effect of SP on viral myocarditis [62]. However, pre- or posttreatment with the Rho inhibitor fasudil did not significantly affect Myocarditis, an inflammatory disorder of the the clinical and pathological manifestations in heart, is most commonly caused by viral infec- EMCV infected mice. The above results reveal tions, such as coxsackie virus, echovirus, ade- that the effects of SP on cardiac-remodeling novirus and picornovirus. Viral myocarditis is and dysfunction following ECMV infection is

12950 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection mediated by its high affinity receptor, but not The role of SP and its receptor in measles the Rho-A pathway, suggesting that SP-receptor virus (MV) infection antagonism may be a novel therapeutic-option for patients with viral-myocarditis. SP inhibits the replication of MV in cultured cells, and partially inhibits viral fusion to the The role of SP in respiratory syncytial virus cells of the hemolysis system. A single 0.6 infection mumol/l, SP treatment inhibited 50% of the MV infection, and the effect was completely revers- After the respiratory syncytial virus (RSV) infect- ible. The antiviral effect of SP is consistent with ed the airway of the guinea pig, the balance of that of the 3- to 7-amino acid synthe- neuropeptide expression in lung neurons was sized by Schroeder C [67], which may have the influenced causing increased airway reactivity. same short sequence as the N-terminus of the The number of SP-positive neurons increased fusion protein with the paramyxovirus (includ- after RSV infection. As airway reactivity is main- ing the MV). SP blocks the spread of the MV tained by the dynamic balance of two different between neurons. The use of NK1-R gene components, excitatory components such as knockout or a drug blocking NK1-R reduces the SP and inhibitory components such as NO and susceptibility of mice to MV, suggesting that VIP, the stimulating inflammatory effects of NK1-R plays a role in MV central nervous infec- SP were strengthened by RSV persistence. At tion and transmission and may be a receptor or the meantime, RSV infection-induced nerve a co-receptor participating in the fusion of MV. growth factor (NGF) and neurotrophic factor In the experiment, most NK1-R-deficient new- expression, thus stimulating SP and NK1-R born mice or normal adult mice treated with expression [63]. In another study, SP expres- aprepitant survived the MV infection, with no sion was markedly increased in mouse airway sign of disease or virus replication in the cen- tissue after RSV infection, consistent with pre- tral nervous system. NK1-R may be a receptor vious research. Prophylactic treatment with for MV in CD46+ neurons, and the SP-mediated Sendide, a highly selective antagonist of the blockade of measles infection may be associ- neurokinin-1 receptor inhibited the develop- ated with SP’s competitive inhibition of NK-1 ment of airway inflammation and airway hyper- receptors [68]. responsiveness (AHR) in RSV-infected animals. Therapeutic treatment with gene- The role of SP and its receptor in Epstein-Barr related peptide abolished AHR in RSV-infected virus (EBV) infection animals despite increased substance P levels and previously established airway inflammation In the study published by Pierson DL and his [64]. Severe bronchitis in RSV-infected pediat- team, the number of copies of EB virus in the ric patients is associated with reduced airway specimens of 32 astronauts during 10 IFN-γ and SP levels. Lower interferon-γ (IFN-γ) air flights averaged 417/ml per air flight, which and SP concentrations were observed in the was significantly higher than the number of nasopharyngeal aspirates of infants in the oxy- copies detected before the flights (40/ml) and gen-dependent and mechanical ventilation after the flights (44/ml) [69]. In a study of 5 groups, and low IFN-γ and SP concentrations in astronauts, the plasma SP concentrations were the nasopharyngeal aspirates have been used higher upon landing than before the flight. The as independent predictors of the severity of the observed elevated SP levels reduced cellular disease [65]. immunity and might have played a role in EB virus activation. Treatments that block SP reduce the apnea time caused by RSV infection The role of SP and its receptor in enterovirus 71 (EV71) infection Apnea is a common complication in RSV- infected infants. In newly weaned rats, the The expression levels of the TAC1 and IL-17A duration of apnea was reduced after selective genes are higher in mononuclear cells in the inhibition of NK1-R. Sensory nerve stimulation peripheral blood of rhesus monkeys infected during RSV infection is related to the occur- with EV71 than in uninfected rhesus monkeys. rence of apnea, and its mechanism is related to EV71 is the main pathogen of hand, foot, and the binding of SP to NK1-R [66]. mouth disease (HFMD), and the TAC1 gene is

12951 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection expressed at higher levels in the central ner- [5] Nawa H, Hirose T, Takashima H, Inayama S and vous system than in the lungs. SP expression is Nakanishi S. Nucleotide sequences of cloned significantly higher in the hypothalamus of rhe- cDNAs for two types of bovine brain substance sus monkeys infected with EV71 virus than in P precursor. Nature 1983; 306: 32-36. uninfected rhesus monkeys, suggesting that [6] Muñoz M and Coveñas R. Involvement of sub- SP may play a role in EV71 virus infection [70]. stance P and the NK-1 receptor in human pa- thology. Amino Acidsv 2014; 46: 1727-1750. Conclusion [7] Fong TM, Anderson SA, Yu H, Huang RR and Strader CD. Differential activation of intracel- SP is a widely distributed tachykinin and brain- lular effector by two isoforms of human neuro- -1 receptor. Mol Pharmacol 1992; 41: 24- gut peptide with important pathophysiological 30. functions. SP and its receptors play important [8] Ho WZ and Douglas SD. Substance P and neu- roles in viral infection, and clinical trials on the rokinin-1 receptor modulation of HIV. J Neuro- use of SP receptor antagonists to combat HIV immunol 2004; 157: 48-55. infection have begun. Nerves are distributed in [9] Douglas SD, Lai JP, Tuluc F, Schwartz L and Kil- a wide range of tissues, and HSK is a type of patrick LE. Neurokinin-1 receptor expression keratitis that is closely related to the nervous and function in human macrophages and system. Because SP is mainly synthesized by brain: perspective on the role in HIV neuro- neurons, SP may play an important role in the pathogenesis. Ann N Y Acad Sci 2008; 1144: course of HSK. A preliminary conclusion is that 90-96. SP combats HSV-1 infection or regulates HSK [10] Meshki J, Douglas SD, Lai JP, Schwartz L, Kil- symptoms; however, further studies of the func- patrick LE and Tuluc F. Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells tion of SP and its receptor in HSK are needed. through a Rho/Rho-associated coiled-coil ki- Acknowledgements nase-dependent mechanism. J Biol Chem 2009; 284: 9280-9289. [11] Chen P, Douglas SD, Meshki J and Tuluc F. The study was funded by National Natural Neurokinin 1 receptor mediates membrane Science fund of China (Fund Number: 8157- blebbing and sheer -induced microparti- 0820) and Huai’an Natural Science Research cle formation in HEK293 cells. PLoS One Project (Fund Number: HAB201738). 2012; 7: e45322. [12] Castagliuolo I, Valenick L, Liu J and Pothoula- Disclosure of conflict of interest kis C. Epidermal growth factor receptor trans- activation mediates substance P-induced mi- None. togenic responses in U-373 MG cells. J Biol Chem 2000; 275: 26545-26550. Address correspondence to: Dr. Hongwei Zhou, [13] Koh YH, Moochhala S and Bhatia M. Activation Department of Ophthalmology, Lianshui County of neurokinin-1 receptors up-regulates sub- People’s Hospital, 6 Hongri Road, Lianshui, Huai’an stance P and neurokinin-1 receptor expression 223400, Jiangsu, China. Tel: 86-15851785316; in murine pancreatic acinar cells. J Cell Mol Fax: 86-517-82321458; E-mail: zhouhongwei@sjtu. Med 2012; 16: 1582-1592. org [14] Castagliuolo I, Morteau O, Keates AC, Valenick L, Wang CC, Zacks J, Lu B, Gerard NP and References Pothoulakis C. Protective effects of neuroki- nin-1 receptor during colitis in mice: role of the [1] V Euler US, Gaddum JH. An unidentified de- epidermal growth factor receptor. Br J Pharma- pressor substance in certain tissue extracts. J col 2002; 136: 271-279. Physiol 1931; 72: 74-87. [15] Koon HW, Zhao D, Zhan Y, Moyer MP and [2] Chang MM and Leeman SE. Isolation of a sial- Pothoulakis C. Substance P mediates anti- ogogic peptide from bovine hypothalamic tis- apoptotic responses in human colonocytes by sue and its characterization as substance P. J Akt activation. Proc Natl Acad Sci U S A 2007; Biol Chem 1970; 245: 4784-4790. 104: 2013-2018. [3] Chang MM, Leeman SE and Niall HD. Amino- [16] Fiebich BL, Schleicher S, Butcher RD, Craig A acid sequence of substance P. Nat New Biol and Lieb K. The neuropeptide substance P ac- 1971; 232: 86-87. tivates p38 mitogen-activated protein kinase [4] Tregear GW, Niall HD, Potts JT Jr, Leeman SE, resulting in IL-6 expression independently from Chang MM. Synthesis of substance P. Nat New NF-kappa B. J Immunol 2000; 165: 5606- Biol 1971; 232: 87-89. 5611.

12952 Int J Clin Exp Med 2018;11(12):12946-12955 Substance P and viral infection

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