Scholarlink

<p>Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (<i>CLEC16A</i>), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte-specific <i>Clec16a</i> inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathological responses and a candidate therapeutic target in MS.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model

  • 期刊论文

  • 发表日期：

    2025年3月3日

查看全文
  • Atsushi Kadowaki,
  • Michael A. Wheeler,
  • Zhaorong Li,
  • Brian M. Andersen,
  • Hong-Gyun Lee,
  • Tomer Illouz,
  • Joon-Hyuk Lee,
  • Alain Ndayisaba,
  • Stephanie E. J. Zandee,
  • Himanish Basu,
  • Chun-Cheih Chao,
  • Joao V. Mahler,
  • Wendy Klement,
  • Dylan Neel,
  • Matthew Bergstresser,
  • Veit Rothhammer,
  • Gabriel Lipof,
  • Lena Srun,
  • Scott A. Soleimanpour,
  • Isaac Chiu,
  • Alexandre Prat,
  • Vikram Khurana,
  • Francisco J. Quintana

摘要

Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (CLEC16A), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte-specific Clec16a inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathological responses and a candidate therapeutic target in MS.