KARAP Exacerbates Intestinal Inflammation Through Promoting Kyn-AhR-dependent Neutrophil Activation in Ulcerative Colitis.

BACKGROUND & AIMS: Killer cell activating receptor-associated protein (KARAP), also known as TYRO protein tyrosine kinase binding protein, has been reported to participate in the regulation of autoimmunity and inflammation. However, the underlying mechanisms involved in intestinal mucosal inflammation in ulcerative colitis (UC) remains obscure.

METHODS

We analyzed KARAP expression in colon tissues from patients with UC and established dextran sulfate sodium (DSS)-induced colitis models in KARAP-knockout (KARAP-/-) mice to determine the potential role of KARAP in the induction of mucosal inflammation. To clarify the immunoregulation of neutrophils on intestinal epithelial barrier function, we cocultured neutrophils isolated from KARAP-/- or wild-type mice with intestinal epithelial cells. Additionally, we profiled neutrophil tryptophan metabolites using targeted metabolomics.

RESULTS

Our data demonstrated that KARAP was highly expressed in the intestinal mucosal tissue and peripheral blood neutrophils of active UC patients, particularly in neutrophils. Inhibition of KARAP promoted anti-inflammatory immune responses in neutrophils in vitro, showing a significant decrease in the expression of proinflammatory cytokines, including IL-6, TNF-α, and IL-1β. Consistently, KARAP deficiency alleviated DSS-induced colitis in mice and improved intestinal mucosal barrier integrity via the aryl hydrocarbon receptor (AhR)-IL-22 pathway in neutrophils. Mechanistically, KARAP deficiency enhanced the nuclear translocation of AhR through the IDO1-kynurenine pathway in neutrophils. Notably, administration of KARAP-/- neutrophils alleviated mucosal inflammation in DSS-induced colitis mice.

CONCLUSIONS

Overall, our study highlights the critical role of KARAP in mucosal inflammation in UC by promoting neutrophil proinflammatory immune responses and disrupting the intestinal mucosal barrier integrity, suggesting that targeting KARAP in neutrophils may represent a novel therapeutic approach for UC.