Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Abstract Inflammatory bowel disease ( IBD ) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD . However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis ( UC ), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell ( ILC 3)–interleukin ( IL )‐22 pathway. In mice, blockade of ectonucleotidases ( NTPD ases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate ( eATP ) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL ‐22‐producing ILC 3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL ‐22. Mechanistically, activation of ILC 3s for IL ‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPD ase‐mediated balance between eATP and adenosine regulates ILC 3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine– ILC 3 axis.