AF6 orchestrates macrophage polarization via JAK2-STAT3 signaling and supports intestinal regeneration by stimulating stem cell proliferation.

INTRODUCTION

Macrophages play a central role in regulating intestinal inflammation, resolution, and tissue repair. However, the upstream regulators that govern their polarization during colitis remain poorly defined.

METHODS

In this study, we used a dextran sulfate sodium (DSS)-induced colitis model to investigate the role of the scaffold protein AF6 in colitis pathogenesis.

RESULTS

We identify AF6 as a key regulator that promotes pro-inflammatory macrophage polarization and exacerbates colitis. Mechanistically, AF6 expression promoted JAK-STAT3 complex formation. In turn, its deletion in macrophages resulted in impaired JAK-STAT3 signaling pathway and a shift away from pro-inflammatory M1 polarization. Furthermore, the AF6-deficient macrophages were determined to also promote epithelial regeneration through enhanced IL-10 production and downstream activation of Wnt/β-catenin signaling in intestinal organoids culture.

DISCUSSION: Thus, our study defines a therapeutically amenable AF6-JAK2-STAT3 axis that controls macrophage-driven pathogenesis in colitis, revealing a novel strategy to break the cycle of inflammation and impaired repair.