Astrocytic Netrin-1 modulates stress-induced anxiety susceptibility in mice through ADAM17-mediated TNFα shedding

Anxiety disorder is one of the most prevalent psychiatric diseases, with stress being a high-risk factor that functions by inducing neuroinflammation, particularly through the release of tumor necrosis factor α (TNFα). Although stress-induced transcription of TNFα is well documented, whether it also controls the proteolytic maturation of membrane-anchored TNFα precursor (proTNFα) remains unknown. Here we showed that the astrocyte-derived extracellular protein Netrin-1 was highly expressed in the mouse medial prefrontal cortex (mPFC) and down-regulated by restraint stress. Conditional knockout (cKO) of astrocytic Netrin-1 in astrocytes, both in embryo and adult, increased susceptibility to stress-induced anxiety. Mechanistically, Netrin-1 interacted with A disintegrin and metalloprotease 17 (ADAM17) and blocked ADAM17-mediated shedding of TNFα from proTNFα. Consequently, Netrin-1 deficiency elevated soluble TNFα and altered microglial morphology. Pharmacological neutralization of TNFα with Infliximab normalized anxiety-like phenotypes in stressed Netrin-1 cKO mice. Collectively, our data identify Netrin-1 as a critical brake on TNFα release and position the Netrin-1–ADAM17 axis as a tractable therapeutic target for TNFα-driven neuropsychiatric disorders.