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<p>Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular stress to microglia-mediated immune responses in MS remain elusive. Stress granules (SGs) serve as an adaptive response of cells to various stressors such as viral infection and oxidative stress. In this study, we found that microglial T-cell intracellular antigen 1 (TIA1), a core SG component, was upregulated in MS patients and experimental autoimmune encephalomyelitis (EAE) mice. The neuroinflammation, demyelination and clinical deficits were exacerbated in <i>Tia1</i><sup>Cx3cr1</sup>-CKO (TIA1 knockout in microglia and monocyte-derived macrophages) EAE mice. Furthermore, TIA1<sup>-/-</sup> microglia exhibited the heightened activation characterized by increased proliferation, enhanced phagocytic activity, and a sustained polarization toward a pro-inflammatory phenotype. Notably, in an in vitro model of NaAsO<sub>2</sub>-induced stress, TIA1 deficiency in BV2 cells and primary cultured microglia resulted in both enhanced phagocytic capacity and a pro-inflammatory phenotypic shift. Mechanistically, upon to stresses, microglial TIA1-mediated SGs formation was enhanced, leading to sequester <i>ApoE</i> mRNA into SGs to reduce ApoE expression, which in turn prevented excessive activation of microglia and inhibited demyelination in EAE mice. These findings uncover a previously unrecognized neuroprotective mechanism wherein TIA1-mediated SGs in microglia dynamically restrain neuroinflammation via post-transcriptional control of ApoE, revealing a new therapeutic avenue for MS.</p>

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An unrecognized mechanism of neuroprotection by microglial TIA1-mediated stress granules to prevent neuroinflammation and demyelination in experimental autoimmune encephalomyelitis mice through sequestering ApoE mRNA

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Qinjiao Fu,
  • Yanzhu Liu,
  • Fangfang Li,
  • Yanjiao Wang,
  • Juanqing Yue,
  • Yingyi Chen,
  • Shufang Wu,
  • Jingjing Zhang,
  • Mengxian Jia,
  • Yaozhi He,
  • Jiawei Wang,
  • Zhihui Huang,
  • Ying Wang

摘要

Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular stress to microglia-mediated immune responses in MS remain elusive. Stress granules (SGs) serve as an adaptive response of cells to various stressors such as viral infection and oxidative stress. In this study, we found that microglial T-cell intracellular antigen 1 (TIA1), a core SG component, was upregulated in MS patients and experimental autoimmune encephalomyelitis (EAE) mice. The neuroinflammation, demyelination and clinical deficits were exacerbated in Tia1Cx3cr1-CKO (TIA1 knockout in microglia and monocyte-derived macrophages) EAE mice. Furthermore, TIA1-/- microglia exhibited the heightened activation characterized by increased proliferation, enhanced phagocytic activity, and a sustained polarization toward a pro-inflammatory phenotype. Notably, in an in vitro model of NaAsO2-induced stress, TIA1 deficiency in BV2 cells and primary cultured microglia resulted in both enhanced phagocytic capacity and a pro-inflammatory phenotypic shift. Mechanistically, upon to stresses, microglial TIA1-mediated SGs formation was enhanced, leading to sequester ApoE mRNA into SGs to reduce ApoE expression, which in turn prevented excessive activation of microglia and inhibited demyelination in EAE mice. These findings uncover a previously unrecognized neuroprotective mechanism wherein TIA1-mediated SGs in microglia dynamically restrain neuroinflammation via post-transcriptional control of ApoE, revealing a new therapeutic avenue for MS.