Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

Description

Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to thepurinergic receptor P2RX7 has emerged as a critical event incontrolling intestinal inflammation, acting to limit elevation ofproinflammatory mast cells and cytokines and promote survival ofregulatory T cells (Treg) and enteric neurons. In this study, weinvestigated the effect of P2RX7 blockade in an established mousemodel of CAC. Using genetic and pharmacologic tools, we foundunexpectedly that while P2RX7 mediated inflammatory responses,it also acted at an early time to suppress CAC development. P2RX7blockade enhanced proliferation of intestinal epithelial cells andprotected them from apoptosis. The proliferative effects of P2RX7blockade were associated with an increased production of TGFb1that was sufficient to stimulate the proliferation of intestinalepithelial cells. Finally, P2RX7 blockade also altered immune cellinfiltration and promoted Treg accumulation within lesions of thedigestive system. Taken together, our findings reveal an unexpectedrole for P2RX7 in preventing CAC, suggesting cautions in the use ofP2RX7 inhibitors to treat IBD given the possibility of increasingrisks CAC as a result.

Abstract

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