IL‐22Rα1 restrains pancreatic injury independently of its C‐terminal STAT3‐amplifying domain

Abstract Interleukin‐22 (IL‐22) is a cytokine that regulates tissue inflammation and repair, primarily through activation of STAT3 signaling. Although its protective effects in acute pancreatitis (AP) are well established, the specific contribution of its receptor, IL‐22Ra1, and the underlying signaling mechanisms remain incompletely defined. Notably, the C‐terminal region of IL‐22Ra1, although devoid of tyrosine residues, has been reported to promote STAT3 activation through unconventional mechanisms. Here, we investigated the role of IL‐22Ra1 and its C‐terminal (STAT3‐associated) domain in a mouse model of caerulein‐induced AP. We show that deletion of the C‐terminal region of IL‐22Ra1 markedly reduces STAT3 activation in the pancreas, confirming its role in amplifying canonical signaling. Unexpectedly, this reduction does not worsen pancreatic injury. In contrast, both IL‐22‐ and IL‐22Ra1‐deficient mice develop more severe pancreatitis, characterized by increased serum amylase levels, exacerbated inflammatory responses, and enhanced tissue damage. Notably, IL‐22Ra1 deficiency results in a more severe phenotype than IL‐22 deficiency alone, indicating that IL‐22Ra1 mediates protective effects beyond IL‐22 signaling. Consistently, acinar‐to‐ductal metaplasia during the regenerative phase is impaired in both IL‐22‐ and IL‐22Ra1‐deficient mice but preserved upon C‐terminal truncation. Together, these findings identify IL‐22Ra1 as a central regulator of pancreatic protection through mechanisms that are independent of maximal STAT3 activation and extend beyond IL‐22 itself, suggesting the involvement of additional IL‐22Ra1 ligands. These results support the exploration of receptor‐activating strategies, such as agonistic antibodies, to promote tissue protection and regeneration.