AF6 deletion reprograms macrophages, boosts intestinal regeneration in DSS-induced colitis model

Macrophages are critical regulators of intestinal inflammation, resolution, and tissue repair, yet the upstream signals governing their polarization during colitis remain poorly understood. An imbalance in macrophage polarization, particularly an excess of pro-inflammatory M1 macrophages, significantly contributes to the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic strategies often focus on suppressing inflammation but frequently fall short in promoting robust tissue repair, leaving a critical gap in addressing both aspects of the disease. Identifying key regulators of macrophage polarization could offer novel targets to break this cycle of inflammation and impaired healing.

Researchers investigated the role of the scaffold protein AF6 in a dextran sulfate sodium (DSS)-induced colitis model. They utilized mice with genetic deletion of AF6 in macrophages to observe its impact on disease progression and resolution. The study assessed macrophage polarization states, specifically focusing on the shift away from pro-inflammatory M1 phenotypes. Furthermore, they explored the regenerative capacity of AF6-deficient macrophages by co-culturing them with intestinal organoids to evaluate epithelial regeneration and associated signaling pathways, including Wnt/β-catenin activation.

AF6 was identified as a pivotal regulator that actively promotes pro-inflammatory macrophage polarization, thereby exacerbating colitis severity. Mechanistically, the presence of AF6 expression significantly promoted the formation of the JAK-STAT3 complex. Conversely, deletion of AF6 specifically in macrophages resulted in a profound impairment of the JAK-STAT3 signaling pathway. This impairment led to a distinct shift away from the pro-inflammatory M1 polarization state, indicating a reprogramming of macrophage function. > AF6-deficient macrophages were found to actively promote epithelial regeneration through enhanced production of the anti-inflammatory cytokine IL-10. This IL-10 production subsequently led to the downstream activation of Wnt/β-catenin signaling within intestinal organoids culture, directly supporting intestinal stem cell proliferation and tissue repair.