Macrophages in Ulcerative Colitis: Immunomodulatory Roles, Phenotypic Switching, and Therapeutic Targeting

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by dysregulated immune responses in the gut. Macrophages, as key innate immune cells in the intestinal mucosa, play a central role in both maintaining homeostasis and driving pathology in UC.

Under physiological conditions, intestinal macrophages exhibit a unique "inflammatory anergy" phenotype, supporting epithelial integrity and immune tolerance. In UC, however, persistent inflammatory signals promote monocyte recruitment and their polarization into pro-inflammatory M1-like macrophages. These cells secrete cytokines such as TNF-α, IL-1β, IL-6, and IL-12/23, produce reactive oxygen species and reactive nitrogen species, and release matrix metalloproteinases, collectively driving epithelial barrier disruption, tissue damage, and sustained inflammation. This review comprehensively discusses the origin, heterogeneity, and functional plasticity of intestinal macrophages, their dynamic interactions with other cells, and key regulatory signaling pathways - such as NF-κB, JAK-STAT, and the NLRP3 inflammasome - in UC.

We evaluate current and emerging macrophage-targeted therapies, including cytokine blockade, chemokine receptor antagonism, phenotypic reprogramming, nanomedicine, and cell-based interventions. Furthermore, we highlight the limitations of the M1/M2 dichotomy and emphasize the need for single-cell and spatial transcriptomic approaches to better define macrophage subsets in human disease. Advancing the understanding of macrophage biology in UC will facilitate the development of precise immunomodulatory strategies and biomarker-based diagnostics, ultimately aiming to bridge the gap between mechanistic discovery and improved patient care.