A161 HEMOPEXIN TREATMENT ALLEVIATES COLITIS SEVERITY IN THE ABSENCE OF IL-22RA1 SIGNALING IN MICE

TL;DR

Hemopexin treatment reduces colitis severity in mice lacking IL-22 signaling, suggesting it could be a new therapeutic option for inflammatory bowel disease.

Contribution

This study demonstrates that hemopexin can alleviate colitis in mice without IL-22 signaling, offering a novel therapeutic approach for IBD.

Findings

Il22ra1-/- mice showed worse colitis symptoms compared to wild-type mice.

Hemopexin treatment reduced disease activity and inflammation in Il22ra1-/- mice.

Hemopexin administration increased gut hemopexin levels and decreased free luminal heme.

Abstract

Inflammatory bowel disease (IBD) is often defined by persistent intestinal epithelial inflammation, bleeding, and pain. It is one of the major risk factors for colorectal cancer (CRC). IBD’s pathogenesis is fundamentally characterized by the release of free luminal heme. Dietary heme induces intestinal dysbiosis and exacerbates colitis. Interleukin 22 (IL-22) is produced in the gut by immune cells, mainly innate lymphoid cell 3 (ILC3). It is known to induce a protective response mediated by hemopexin, a plasma heme scavenger produced in the liver that limits the availability of heme iron to microbes and suppresses bacterial growth.

To evaluate the protective role of IL-22 by the stimulation of hemopexin in a mouse model of acute colitis

To assess the effect of IL-22 on colitis, Il22ra1-/- and wild-type (Wt) mice on a C57BL/6 background were treated with 2.5% dextran sodium sulphate (DSS) in drinking water for 12 days to induce colitis, after which they were sacrificed. To reverse colitis severity with hemopexin, three groups of mice received 2.5% DSS in drinking water for 12 days. The treatment group (Il22ra1-/-) received an 15 mg/kg BW hemopexin injection intraperitoneally on day 7 of the DSS treatment, while the other two groups, Wt and Il22ra1-/-, received the vehicle (PBS).

Il22ra1

-/-
mice had significantly greater weight loss, higher disease activity index (DAI) score and shorter colon length on day 12 (endpoint) compared to the Wt mice. Significant increases in inflammatory markers such as lipocalin-2 (lcn-2), TNF-α and IL-6 were observed in Il22ra1-/- mice, contributing to their condition. Decreased fecal hemopexin and increased free luminal heme were observed in Il22ra1-/- mice compared to the Wt mice. Hemopexin administration reversed the disease severity by reducing DAI, inflammatory markers and increasing the colon length. Increased fecal hemopexin and reduced luminal heme were also observed in the Il22ra1-/- mice.

Hemopexin is present in the gut during colitis. The absence of Il-22ra1 enhances free luminal heme production, reduces hemopexin concentration in the gut, and aggravates colitis in mice. Hemopexin administration reduces free luminal heme in the gut, enhances hemopexin availability and alleviates colitis severity in mice.

CIHRUniversite de Montreal, CRCHUM, Institute du Cancer de Montreal