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<p>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 <i>Netrin-1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Yue Yin,
  • Xiu Liu,
  • Jun Ma,
  • Mei-Lin Liu,
  • Lin-Sheng Yi,
  • Jin-Ting Ni,
  • Meng-Jie Xing,
  • Jing Yang,
  • Meng Tian,
  • Jia-ai Zhang,
  • Wen-Bing Chen,
  • Xiao-Xiao He,
  • Zi-Xuan He,
  • Ze-zhong Wang,
  • Xiao-Juan Zhu,
  • Hua-Li Yu

摘要

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.