Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer
Abstract
Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the
purinergic receptor P2RX7 has emerged as a critical event in
controlling intestinal inflammation, acting to limit elevation of
proinflammatory mast cells and cytokines and promote survival of
regulatory T cells (Treg) and enteric neurons. In this study, we
investigated the effect of P2RX7 blockade in an established mouse
model of CAC. Using genetic and pharmacologic tools, we found
unexpectedly that while P2RX7 mediated inflammatory responses,
it also acted at an early time to suppress CAC development. P2RX7
blockade enhanced proliferation of intestinal epithelial cells and
protected them from apoptosis. The proliferative effects of P2RX7
blockade were associated with an increased production of TGFb1
that was sufficient to stimulate the proliferation of intestinal
epithelial cells. Finally, P2RX7 blockade also altered immune cell
infiltration and promoted Treg accumulation within lesions of the
digestive system. Taken together, our findings reveal an unexpected
role for P2RX7 in preventing CAC, suggesting cautions in the use of
P2RX7 inhibitors to treat IBD given the possibility of increasing
risks CAC as a result.