FOXP3 + Macrophage‐Derived Amphiregulin Promotes White Matter Repair of Experimental Autoimmune Encephalomyelitis

ABSTRACT Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination followed by varying degrees of remyelination. Macrophages play a pivotal role in both processes. Understanding how macrophages modulate their plasticity to facilitate remyelination in MS holds significant therapeutic potential, yet this mechanism remains poorly understood. In this study, we demonstrate that the digestion of myelin debris by macrophages triggers the activation of FOXP3 signaling, which induces a pro‐regenerative phenotype. Specifically, we generated macrophage‐specific Foxp3 conditional knockout mice and show that FOXP3 + macrophages promote oligodendrocyte progenitor cell differentiation by producing amphiregulin (AREG), a neurotrophic factor. This mechanism enhances recovery in experimental autoimmune encephalomyelitis. These findings suggest that FOXP3 + macrophages could serve as a promising therapeutic target in MS.