title: P2X7 receptor promotes intestinal inflammation in chemically induced colitis and triggers death of mucosal regulatory T cells.
abstract: P2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors. P2X7 KO mice were protected against gut inflammation induced by 2,4,6-trinitrobenzenesulfonic acid or oxazolone, with no weight loss or gut histological alterations after treatment. P2X7 receptor knockout induced regulatory T cell accumulation in the colon, as evaluated by qRT-PCR for FoxP3 expression and immunostaining for CD90/CD45RBlow. Flow cytometry analysis of mesenteric lymph node cells showed that P2X7 activation (by ATP) triggered regulatory T cell death. In addition, such cells from P2X7 KO mice expressed more CD103, suggesting increased migration of regulatory T cells to the colon (relative to the WT). Our results show that the P2X7 has a key role during inflammation development in inflammatory bowel disease, by triggering the death and retention in the mesenteric lymph nodes of regulatory T cells that would otherwise promote immune system tolerance in the gut.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil; Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Vanessa R
authors.initials: VR
authors.lastname: Figliuolo
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Luiz Eduardo Baggio
authors.initials: LEB
authors.lastname: Savio
authors.affiliation: Interactions Cellulaires et Physiopathologie Hépatique, UMRS 1174 INSERM, Université Paris Sud, Orsay, France; Centre de la recherche sur l'inflammation, UMR 1149 INSERM, Université Paris Diderot, Paris, France.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Safya
authors.affiliation: Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Hayandra
authors.initials: H
authors.lastname: Nanini
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Cláudio
authors.initials: C
authors.lastname: Bernardazzi
authors.affiliation: Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Abalo
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Heitor S P
authors.initials: HSP
authors.lastname: de Souza
authors.affiliation: Institut de Biologie intégrative de la cellule, Centre National de la Recherche Scientifique, I2BC - CNRS/UMR9198, Université Paris-Sud, Orsay, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Kanellopoulos
authors.affiliation: Interactions Cellulaires et Physiopathologie Hépatique, UMRS 1174 INSERM, Université Paris Sud, Orsay, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bobé
authors.affiliation: Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil.
authors.forename: Cláudia M L M
authors.initials: CMLM
authors.lastname: Coutinho
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil. Electronic address: rcsilva@biof.ufrj.br.
authors.forename: Robson
authors.initials: R
authors.lastname: Coutinho-Silva
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D018928:Immunity, Mucosal; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010081:Oxazolone / Q000009:adverse effects / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D058486:Receptors, Purinergic P2X7; D010081:Oxazolone; D014302:Trinitrobenzenesulfonic Acid
keywords: ATP; Colitis, regulatory T cells; P2X7 receptor