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<p>The pathological processes of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are closely associated with excessive activation of inflammasomes. HSPA8 is a constitutively expressed molecular chaperone involved in cellular signaling and immune-inflammatory regulation, but its role in EAE-associated neuroinflammation remains unclear. In this study, we found that HSPA8 was significantly upregulated in the spinal cord tissues of EAE mice and positively correlated with disease severity. Immunofluorescence co-staining showed that HSPA8 upregulation was more prominently associated with Iba1-positive microglia/macrophage-enriched regions than with GFAP- or NeuN-positive regions. Intrathecal knockdown of HSPA8 attenuated EAE progression, reduced inflammatory responses, and alleviated demyelination and axonal injury. In vitro, HSPA8 knockdown reduced NLRP3 inflammasome-mediated IL-1β/IL-18 release, caspase-1 activation, GSDMD-N formation, and pyroptosis in THP-1 cells, bone marrow-derived macrophages, and BV2 microglia, and these effects were partially restored by siRNA-resistant HSPA8 rescue. Mechanistically, HSPA8 knockdown was associated with impaired NF-κB-dependent priming, as reflected by reduced p65 phosphorylation, nuclear translocation, NF-κB transcriptional activity, and pro-IL-1β expression. HSPA8 is also associated with ASC, and HSPA8 knockdown impaired NLRP3–ASC interaction, ASC oligomerization, and ASC speck formation during inflammasome assembly. These findings suggest that HSPA8 is functionally associated with NLRP3 inflammasome activation through both NF-κB‑dependent priming and ASC‑associated assembly, thereby contributing to neuroinflammation in EAE. HSPA8 may represent a potential therapeutic target for MS-related and other inflammasome-driven neuroinflammatory disorders.</p>

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Inhibition of HSPA8 alleviates experimental autoimmune encephalomyelitis via dual modulation of NLRP3 inflammasome activation: suppressing both NF-κB–mediated priming and ASC-dependent assembly

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月24日

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  • Qianqian Bai,
  • Yan Guo,
  • Shunji Pan,
  • Fangfei Liu,
  • Wenchao Tang,
  • Xiaozhi Bai,
  • Shumin Zhang,
  • Xiaoyu Ma,
  • Qizhi Fu,
  • Dongmei Wang,
  • Hua Fan

摘要

The pathological processes of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are closely associated with excessive activation of inflammasomes. HSPA8 is a constitutively expressed molecular chaperone involved in cellular signaling and immune-inflammatory regulation, but its role in EAE-associated neuroinflammation remains unclear. In this study, we found that HSPA8 was significantly upregulated in the spinal cord tissues of EAE mice and positively correlated with disease severity. Immunofluorescence co-staining showed that HSPA8 upregulation was more prominently associated with Iba1-positive microglia/macrophage-enriched regions than with GFAP- or NeuN-positive regions. Intrathecal knockdown of HSPA8 attenuated EAE progression, reduced inflammatory responses, and alleviated demyelination and axonal injury. In vitro, HSPA8 knockdown reduced NLRP3 inflammasome-mediated IL-1β/IL-18 release, caspase-1 activation, GSDMD-N formation, and pyroptosis in THP-1 cells, bone marrow-derived macrophages, and BV2 microglia, and these effects were partially restored by siRNA-resistant HSPA8 rescue. Mechanistically, HSPA8 knockdown was associated with impaired NF-κB-dependent priming, as reflected by reduced p65 phosphorylation, nuclear translocation, NF-κB transcriptional activity, and pro-IL-1β expression. HSPA8 is also associated with ASC, and HSPA8 knockdown impaired NLRP3–ASC interaction, ASC oligomerization, and ASC speck formation during inflammasome assembly. These findings suggest that HSPA8 is functionally associated with NLRP3 inflammasome activation through both NF-κB‑dependent priming and ASC‑associated assembly, thereby contributing to neuroinflammation in EAE. HSPA8 may represent a potential therapeutic target for MS-related and other inflammasome-driven neuroinflammatory disorders.