IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis

TLDR

IL‑22 is upregulated in inflammatory bowel disease, yet its receptor is confined to innate immune cells and its role in colitis remains undefined. The study sought to create a microinjection‑based local gene‑delivery system to target IL‑22 to the inflamed intestine. The authors employed this microinjection system to deliver IL‑22 or its binding protein directly into colonic tissue. IL‑22 gene delivery activated STAT3 in colonic epithelial cells, restored mucus‑producing goblet cells, and rapidly ameliorated intestinal inflammation in a Th2‑mediated colitis mouse model, whereas IL‑22‑binding protein reversed these effects, underscoring IL‑22’s therapeutic potential for ulcerative colitis.

Abstract

Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22–mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22–binding protein. Treatment with IL-22–binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium–induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene–delivery system for treating UC.