Related Experiment Video
Updated: Sep 26, 2026
Analyzing Beneficial Effects of Nutritional Supplements on Intestinal Epithelial Barrier Functions During Experimental Colitis
Published on: January 5, 2017
KARAP Exacerbates Intestinal Inflammation Through Promoting Kyn-AhR-dependent Neutrophil Activation in Ulcerative
Guiyuan Jin1, Fengqin Zhu2, Fengxian Dai2
1Taishan Scholars Laboratory, Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China.
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.
Related Concept Videos
01:20Inflammatory Bowel Disease II: Ulcerative Colitis
01:25Inflammatory Bowel Disease III: Crohn's Disease
01:26Gastritis II: Pathophysiology
01:22Pathophysiology of Peptic Ulcer Disease: Injurious Factors
In the antrum region, G cells secrete the gastrin hormone that binds to gastrin-cholecystokinin-B (CCK2) receptors on parietal and enterochromaffin-like (ECL) cells in the fundic glands. Simultaneously, the vagus nerve releases acetylcholine, which binds to M3...
01:17Gastritis-II: Pathophysiology
In acute gastritis, the gastric mucosa becomes swollen and red and undergoes superficial erosion. Superficial ulceration may lead to bleeding.
In chronic gastritis, persistent or repeated insults lead to chronic inflammatory changes and, eventually, thinning or atrophy of the gastric tissue.
Gastritis can stem from various causes, each...
01:27Inflammatory Bowel Disease I: Ulcerative Colitis
Inflammatory bowel disease, or IBD, encompasses a group of disorders characterized by chronic inflammation or ulceration of the gastrointestinal tract.
Risk Factors
The exact cause of IBD remains unclear, although it is believed to be due to a mix of genetic, environmental, microbial, and immune factors. Genetic factors are significant in determining susceptibility to IBD, with family history being a critical risk factor. Individuals with a first-degree relative who has IBD are at...