Deficiency of the innate immune protein IFITM3 impairs phagocytosis and promotes autism-like behaviors in mice.

Abstract

Interferon-induced transmembrane protein 3 (IFITM3) plays a protective role in autism spectrum disorder (ASD), a condition characterized by neuronal degradation and loss. The clearance of apoptotic neurons via efferocytosis activates resolution signaling pathways, driven by phagolysosome-mediated degradation of dying cells. We found that this degradation by phagolysosomal IFITM3 activates the Mer receptor tyrosine kinase/ musculoaponeurotic fibrosarcoma oncogene family B pathway, which drives the proliferation of anti-inflammatory microglia. This efferocytosis-induced microglial proliferation (EIMP) promotes the expansion of resolving microglia. In dexamethasone-induced regression models, IFITM3 depletion inhibits EIMP, reduces apoptotic neuron clearance, and hinders tissue resolution. In conclusion, IFITM3 promotes apoptotic neuron clearance and EIMP in ASD, thereby mediating the resolution of inflammation. These findings suggest that IFITM3 could serve as a potential therapeutic target for modulating neuroinflammation in ASD.