title: P2X7 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome.
abstract: The ATP-gated P2X(7) receptor (P2X(7)R) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release. Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome. In this study, we used P2X(7)R knockout mice (P2X(7)R(-/-)) to investigate the role of P2X(7)R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse. During acute nematode infection, IL-1β-containing cells and P2X(7)R expression were increased in the jejunum of wild-type (WT) mice. Peritoneal and serum IL-1β levels were also increased, which was indicative of elevated IL-1β release. However, in the P2X(7)R(-/-) animals, we found that infection had no effect upon intracellular, plasma, or peritoneal IL-1β levels. Conversely, infection augmented peritoneal TNF-α levels in both WT and P2X(7)R(-/-) animals. Infection was also associated with a P2X(7)R-dependent increase in extracellular peritoneal lactate dehydrogenase, and it triggered immunological changes in both strains. Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X(7)R(-/-) animals. Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli; however, this did not develop in postinfected P2X(7)R(-/-) animals. Therefore, our results demonstrated that P2X(7)Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity.
authors.affiliation: Department of Biomedical Sciences, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Keating
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrin
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Martínez
authors.forename: David
authors.initials: D
authors.lastname: Grundy
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D043183:Irritable Bowel Syndrome / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017160:Trichinella spiralis / Q000276:immunology*; D014235:Trichinellosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017833:Visceral Afferents / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; C546469:P2rx7 protein, mouse; D058486:Receptors, Purinergic P2X7