CCL5 deficiency aggravates acute DSS-induced colitis by restricting IL-33-induced formation of Tregs in intestinal tract.

Abstract

Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, characterized by ongoing intestinal inflammation, epithelial damage, and mucosal injury. Despite the identification of C-C motif chemokine ligand 5 (CCL5) as a key mediator in UC, the precise mechanisms underlying its role in immune activation and inflammation remain unclear. This study aimed to investigate CCL5 as a critical immune modulator in UC, focusing on its effects on immune cell activation, particularly regulatory T cell (Treg) formation, and the molecular pathways involved in these processes. Using the dextran sulfate sodium salt (DSS)-induced UC model and CCL5 knockout (Ccl5-KO) mice, we demonstrated that CCL5 deficiency exacerbates intestinal inflammation during the acute phase of colitis, partly due to impaired interleukin-33 (IL-33)-induced Treg formation. In addition, we observed a positive correlation between CCL5 expression and forkhead box protein 3 (FOXP3) levels in inflamed colon tissues of UC patients, suggesting a role for CCL5 in Treg regulation. Mechanistically, CCL5 deficiency disrupted the PI3K/Akt/NF-κB signaling pathway, resulting in reduced IL-33 expression, which in turn impaired CD4+ T cell activation and FOXP3+ Treg formation via the JAK1/STAT5 pathway. In vivo rescue experiments confirmed that restoring IL-33 signaling could alleviate inflammation and partially recover Treg function. Collectively, these findings highlight CCL5 as a novel immune modulator of Treg formation and immune responses in UC and suggest that targeting CCL5 may offer a promising therapeutic strategy for managing UC and related inflammatory diseases.