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/CD45RB. 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.

Purinergic Signalling: Therapeutic Developments

“…P2X7R agonists are involved in colonic motor dysfunction associated with bowel inflammation in rats ( Antonioli et al, 2014b ) and are over-expressed in gut mucosa of patients with IBD. P2X7R KO mice are protected against gut inflammation ( Figliuolo et al, 2017b ). ATP activates mast cells, which further promote the inflammatory process ( Kurashima and Kiyono, 2016 ).…”

“…The P2X7R antagonist, A438079, down-regulated the production of proinflammatory cytokines and attenuated murine colitis, indicating that P2X7R mediate inflammatory responses during UC ( Wan P. et al, 2016 ). Activation of P2X7R triggers the death of mucosal regulatory T cells ( Figliuolo et al, 2017b ). There was P2XR enhancement in an animal model of UC.…”

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

“…Therefore, targeting eATP-mediated mast-cell activation might be a promising novel strategy for the prevention and treatment of intestinal inflammation [70]. In another setting, eATP-P2X7R induced the death of regulatory T cells (Treg), which suppress colitis [63,71]. Moreover, eATP released from commensal bacteria activates a unique subset of lamina proprial antigen-presenting cells (CD70 high CD11c low cells), leading to the differentiation of Th17 cells (Figure 1).…”

Purinergic drug targets for gastrointestinal disorders

“…P2X7R is over-expressed in IBD patients’ gut mucosa. P2X7R knockout mice were protected against gut inflammation (Figliuolo et al, 2017). P2X7R activates the NLRP3 inflammasome in T cells, macrophages, dendritic cells, and neutrophils (Gombault et al, 2012).…”

“…Colitis differentially affects P2X7R-expressing enteric neurons based on their chemical codes (da Silva et al, 2015). P2X7R activation also triggers mucosal regulatory T cell death (Figliuolo et al, 2017). P2X7R antagonist A438079 35 down-regulates the production of pro-inflammatory cytokines in colonic tissues, and attenuates murine colitis, indicating P2X7R-dependent triggering of immune responses during colitis (Wan et al, 2016b).…”