Macrophage extracellular traps impair intestinal barrier function in DSS-induced colitis in mice by inducing intestinal epithelial cell apoptosis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with recurrent mucosal inflammation in the colon, with macrophages emerging as one of the key effector cells in its pathogenesis. Recently, macrophage extracellular traps (METs), mediated by peptidyl arginine deiminase 4 (PAD4), have emerged as potential contributors to inflammatory disorders. However, the specific mechanism by which METs contribute to the development and progression of UC remains unclear. In this study, we identified a significant presence of METs in the colonic tissues of clinical UC patients. Moreover, we found that elevated MET formation in DSS-induced UC mice correlates with increased Apoptosis in colonic epithelial cells. Combining RNA Sequencing and Western blot analysis, we demonstrated that METs activate the cGAS-STING pathway in MC38 cells, resulting in reduced cell viability, enhanced Apoptosis, and decreased expression of tight junction proteins in a dose- and time-dependent manner. Furthermore, genetic knockout of PAD4, which inhibits MET formation, attenuated DSS-induced colitis by reducing Apoptosis and enhancing barrier function. Our findings provide novel insights into the role of PAD4-mediated MET formation in UC progression and highlight its potential as a therapeutic target for UC.

Apoptosis; Intestinal epithelial cells; Macrophage extracellular traps; Peptidyl arginine deiminase 4; Ulcerative colitis; cGAS-STING.