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<p>The Sonic Hedgehog (Shh)–Gli1 signaling axis is essential for neuronal development, cell proliferation and homeostasis. However, its roles in microglial activation and neuroinflammation remain poorly defined. Here, we report that Shh is expressed in neurons and astrocytes and is markedly upregulated in the substantia nigra of MPTP-challenged Parkinson’s disease (PD) mouse models. In contrast, microglia do not produce Shh but express its receptor Patched1 (PTCH1) and downstream effectors, including Smoothened (SMO) and Gli1. Exogenous treatment with recombinant Shh or the SMO agonist SAG induced low-level microglial activation and amplified LPS-driven inflammatory responses via the Shh–Gli1–IKKβ signaling pathway. Moreover, we found that Shh–Gli1 signaling contributes to LPS-induced microglial activation. Genetic or pharmacological inhibition of this pathway suppressed microglial activation by attenuating NF-κB signaling. Notably, treatment with the small-molecule SMO inhibitor GDC-0449 (vismodegib) alleviated neuroinflammation and protected dopaminergic neurons in mice subjected to intracranial LPS challenge. Conversely, microglia-specific Ptch1 knockout exacerbated susceptibility to LPS-induced neuroinflammation and dopaminergic neuronal loss. Collectively, these findings demonstrate that microglial Shh–Gli1 signaling promotes microglial inflammatory activation, establishing the pivotal role of this pathway in microglia-driven neuroinflammation and subsequent dopaminergic neuronal injuries.</p>

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Sonic Hedgehog-Gli1 signaling promotes microglial activation via the IKKβ/NF-κB pathway

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Zhi-rou Xu,
  • Kan Wu,
  • Rui-ying Guo,
  • Peng Wang,
  • Jia-wei Ou-Yang,
  • Zhong-qiang Cao,
  • Hui-cui Yang,
  • Jong-Heon Kim,
  • Xiao-hu Zhang,
  • Kyoungho Suk,
  • Xue-chu Zhen,
  • Yuan Wang,
  • Xiang-dong Du,
  • Long-tai Zheng

摘要

The Sonic Hedgehog (Shh)–Gli1 signaling axis is essential for neuronal development, cell proliferation and homeostasis. However, its roles in microglial activation and neuroinflammation remain poorly defined. Here, we report that Shh is expressed in neurons and astrocytes and is markedly upregulated in the substantia nigra of MPTP-challenged Parkinson’s disease (PD) mouse models. In contrast, microglia do not produce Shh but express its receptor Patched1 (PTCH1) and downstream effectors, including Smoothened (SMO) and Gli1. Exogenous treatment with recombinant Shh or the SMO agonist SAG induced low-level microglial activation and amplified LPS-driven inflammatory responses via the Shh–Gli1–IKKβ signaling pathway. Moreover, we found that Shh–Gli1 signaling contributes to LPS-induced microglial activation. Genetic or pharmacological inhibition of this pathway suppressed microglial activation by attenuating NF-κB signaling. Notably, treatment with the small-molecule SMO inhibitor GDC-0449 (vismodegib) alleviated neuroinflammation and protected dopaminergic neurons in mice subjected to intracranial LPS challenge. Conversely, microglia-specific Ptch1 knockout exacerbated susceptibility to LPS-induced neuroinflammation and dopaminergic neuronal loss. Collectively, these findings demonstrate that microglial Shh–Gli1 signaling promotes microglial inflammatory activation, establishing the pivotal role of this pathway in microglia-driven neuroinflammation and subsequent dopaminergic neuronal injuries.