TRAIL Deficiency Impairs Macrophage Differentiation and Aggravates Colitis in Mice 

<title>Abstract</title> <p> Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is widely expressed in immune cells and is crucial for maintaining intestinal immune homeostasis. Resident or proinflammatory macrophages with functional plasticity in the gut play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). This study was to explore the relationship between TRAIL deficiency and IBD disease activity, as well as the impact on the phenotype and function of macrophages in experimental colitis in mice.TRAIL expression in UC and control tissues from the Gene Expression Omnibus (GEO) database and correlated levels with biologic treatment outcomes were analyzed. Using dextran sodium sulfate (DSS) to construct the colitis model in mice, comparative <italic>TRAIL</italic> ^{<italic>−/−</italic>} mice and wild-type (WT) mice inflammation of the colon. Colonic tissue CD11b ⁺ macrophages were quantified by immunofluorescence, and intestinal resident macrophages (CD11b ⁺ CX3CR1 ^high ) and pro-inflammatory macrophages (CD11b ⁺ CX3CR1 ^int ) in colonic lamina propria mononuclear cells (LPMCs) were assessed by flow cytometry. Cytokine expression, including IL-6, IL-1β, TNF-α, and IL-10, in colonic tissues were evaluated by qRT-PCR and ELISA.IBD patients exhibit elevated intestinal TRAIL expression, which significantly correlates with disease severity and the efficacy of biologic treatment. Compared to WT mice, <italic>TRAIL</italic> ^{<italic>−/−</italic>} mice developed more severe colitis. TRAIL deficiency was associated with a rise of pro-inflammatory CD11b ⁺ CX3CR1 ^int macrophages and a decline of resident CD11b ⁺ CX3CR1 ^hi macrophages in the colon, along with increased expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines.TRAIL deficiency may promote the differentiation of macrophages towards a pro-inflammatory phenotype in colitis. Targeting TRAIL may represent a potential therapeutic approach for IBD. </p>