Lipidated IL-22 Alone or Combined with Immunomodulatory Agents Improves Disease Endpoints and Promotes Mucosal Healing in a Mouse Model of Chronic Dextran Sodium Sulfate-Induced Colitis

IL-22 facilitates mucosal healing by directly inducing epithelial regeneration and barrier integrity, which is essential for achieving remission and thereby treating inflammatory bowel disease. Here, we evaluated efficacy of a novel lipidated IL-22 alone and in combination with immunomodulatory agents in addressing chronic dextran sodium sulfate (DSS)-induced colitis in mice and demonstrated action of IL-22 on mucosal healing. Mice were treated with DSS, followed by various doses of lipidated IL-22, anti-TNF antibody, fingolimod, or anti-mouse α4β7 integrin antibody. Additionally, gene expression was determined in colonic biopsies from ulcerative colitis patients to assess effects of IL-22 stimulation. Lipidated IL-22 significantly improved all aspects of chronic DSS-induced colitis in mice, with dose-dependent efficacy. Combinations of a range of immunomodulatory agents with lipidated IL-22 showed further additive reductions in disease activity, significantly greater than those of monotherapies. Immunohistochemistry revealed that lipidated IL-22 increased epithelial cell proliferation and reduced CD3 + T-cell infiltration, indicating enhanced mucosal healing. This was further supported gene expression data from colonic biopsies from ulcerative colitis patients after IL-22 stimulation. Given the challenges in achieving long-term remission in IBD due to inflammation and mucosal damage, lipidated IL-22 presents a promising treatment option that directly promotes mucosal healing, unlike traditional immunomodulatory therapies.