title: Investigating the role of MRGPRC11 and capsaicin-sensitive afferent nerves in the anti-influenza effects exerted by SLIGRL-amide in murine airways.
abstract: The hexapeptide SLIGRL-amide activates protease-activated receptor-2 (PAR-2) and mas-related G protein-coupled receptor C11 (MRGPRC11), both of which are known to be expressed on populations of sensory nerves. SLIGRL-amide has recently been reported to inhibit influenza A (IAV) infection in mice independently of PAR-2 activation, however the explicit roles of MRGPRC11 and sensory nerves in this process are unknown. Thus, the principal aim of this study was to determine whether SLIGRL-amide-induced inhibition of influenza infection is mediated by MRGPRC11 and/or by capsaicin-sensitive sensory nerves.
  
  
  
  The inhibitory effect of SLIGRL-amide on IAV infection observed in control mice in vivo was compared to effects produced in mice that did not express MRGPRC11 (mrgpr-cluster∆ (-/-) mice) or had impaired sensory nerve function (induced by chronic pre-treatment with capsaicin). Complementary mechanistic studies using both in vivo and ex vivo approaches investigated whether the anti-IAV activity of SLIGRL-amide was (1) mimicked by either activators of MRGPRC11 (BAM8-22) or by activators (acute capsaicin) or selected mediators (substance P, CGRP) of sensory nerve function, or (2) suppressed by inhibitors of sensory nerve function (e.g. NK1 receptor antagonists).
  
  
  
  SLIGRL-amide and BAM8-22 dose-dependently inhibited IAV infection in mrgpr-cluster∆ (-/-) mice that do not express MRGPRC11. In addition, SLIGRL-amide and BAM8-22 each inhibited IAV infection in capsaicin-pre-treated mice that lack functional sensory nerves. Furthermore, the anti-IAV activity of SLIGRL-amide was not mimicked by the sensory neuropeptides substance P or CGRP, nor blocked by either NK1 (L-703,606, RP67580) and CGRP receptor (CGRP8-37) antagonists. Direct stimulation of airway sensory nerves through acute exposure to the TRPV1 activator capsaicin also failed to mimic SLIGRL-amide-induced inhibition of IAV infectivity. The anti-IAV activity of SLIGRL-amide was mimicked by the purinoceptor agonist ATP, a direct activator of mucus secretion from airway epithelial cells. Additionally, both SLIGRL-amide and ATP stimulated mucus secretion and inhibited IAV infectivity in mouse isolated tracheal segments.
  
  
  
  SLIGRL-amide inhibits IAV infection independently of MRGPRC11 and independently of capsaicin-sensitive, neuropeptide-releasing sensory nerves, and its secretory action on epithelial cells warrants further investigation.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, 6009, Australia.|School of Anatomy, Physiology & Human Biology, University of Western Australia, Crawley, 6009, WA, Australia.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Chang
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, 6009, Australia.
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Mann
authors.affiliation: School of Anatomy, Physiology & Human Biology, University of Western Australia, Crawley, 6009, WA, Australia.
authors.forename: Peter K
authors.initials: PK
authors.lastname: McFawn
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, 6009, Australia. peter.henry@uwa.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Henry
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006801:Humans; D066298:In Vitro Techniques; D009980:Influenza A virus / Q000472:pathogenicity*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D009842:Oligopeptides / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014132:Trachea / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000821:virology
chemical_list: D000255:Adenosine Triphosphate; D000998:Antiviral Agents; D002211:Capsaicin; D009842:Oligopeptides; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C470192:Mrgprx1 protein, mouse; C571042:bovine adrenal medulla 8-22; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
keywords: Airway sensory nerves; Capsaicin; Influenza; Mas-related G protein-coupled receptor C11; Mucin; Neuropeptides; SLIGRL-amide