Numb attenuates LPS-induced neuroinflammation via autophagic regulation of Ifi204 in microglia

Hippocampal neuroinflammation is a key contributor to cognitive deficits in multiple neurological disorders, yet the intrinsic mechanisms that restrain excessive microglial activation remain incompletely understood. Numb, which is highly expressed in hippocampal microglia, is identified here as an important modulator of inflammatory responses. We show that Numb expression is reduced under neuroinflammatory conditions, and that conditional knockout of Numb in microglia in lipopolysaccharide-exposed mice leads to enhanced neuroinflammation, neuronal injury, and inflammation-associated behavioral impairments. In vitro, Numb deficiency in microglia enhances inflammatory responses and consequently promotes microglia-mediated neuronal damage. At the mechanistic level, Numb interacts with the innate immune sensor Ifi204 and suppresses Ifi204–TLR4 signaling under inflammatory conditions. Moreover, Numb deficiency impairs autophagic flux and reduces lysosomal acidification, accompanied by increased Ifi204 accumulation. Collectively, these findings establish microglial Numb as an intrinsic checkpoint that restrains hippocampal neuroinflammation and preserves neuronal integrity, thereby highlighting its potential as a therapeutic target for cognitive dysfunction associated with neuroinflammatory conditions. • Microglial Numb loss exacerbates hippocampal inflammation and deficits. • Numb restrains microglial activation as an intrinsic checkpoint. • Numb interacts with Ifi204 to suppress TLR4 signaling. • Numb promotes autophagic–lysosomal degradation of Ifi204. • Numb deficiency enhances microglia-mediated neuronal injury.