Hemopexin and HO-1 induction during acute colitis in mice is dependent on interleukin-22

Ayodeji Samuel Ajayi¹Claire Gerkins¹Gabriela Fragoso¹Annie Calvé¹Manuela M Santos^1,2*

• ¹Nutrition and Microbiome Laboratory, Montreal Cancer Institute, University of Montreal Hospital Centre (CRCHUM), Montreal, Canada
• ²Département de Médecine, Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that frequently requires long-term immunosuppressive therapy, which increases the risk of infections and other complications. During active disease, intestinal bleeding is common and leads to the release of free luminal heme, a pro-inflammatory molecule that can disrupt mucosal integrity, fuel microbial dysbiosis, and amplify inflammation. Interleukin-22 (IL-22) plays a protective role in the gut by promoting epithelial barrier integrity and wound healing. More recently, IL-22 has been shown to induce hemopexin, a heme scavenger protein that limits heme availability and suppresses bacterial growth during systemic infections. Here we investigate the protective role of IL-22 and hemopexin in the context of colitis using the dextran sodium sulphate (DSS) acute colitis model in mice. Wild-type (Wt) and Il22ra1 -/-mice were used to evaluate the effects of exogenous hemopexin and hemin treatments on colitis severity. IL-22 signaling was crucial for the induction of hemopexin in the colon, as Il22ra1 -/-mice exhibited limited hemopexin induction and more severe colitis, which could be reversed by recombinant hemopexin administration. Additionally, hemin treatment, known to upregulate heme oxygenase-1 (HO-1), failed to show full protective effects in Il22ra1 -/-mice, suggesting that IL-22 signaling contributes to the anti-inflammatory and antioxidant effects of hemin by inducing hemopexin and HO-1. These findings reveal a critical protective role for IL-22 by increasing the amount of hemopexin and HO-1 production in the colon, which could be part of a protective mechanism that mitigates DSS-induced colonic inflammation. Given its epithelial-specific and immunomodulatory activity, IL-22 represents a promising therapeutic approach for IBD. Furthermore, hemopexin itself may serve as an adjunct therapy during active disease.