Scholarlink

<p>Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB<sup>+</sup> microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures. These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination. Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression. Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.</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

Foamy microglia link oxylipins to disease progression in multiple sclerosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月21日

查看全文
  • Daan van der Vliet,
  • Xinyu Di,
  • Tatiana M. Shamorkina,
  • Claire Coulon-Bainier,
  • Anto Pavlovic,
  • Iris A. C. M. van der Vliet,
  • Yingyu Zeng,
  • Will Macnair,
  • Noëlle van Egmond,
  • J. Q. Alida Chen,
  • Aletta M. R. van den Bosch,
  • Hendrik J. Engelenburg,
  • Dennis Wever,
  • Matthew R. J. Mason,
  • Wouter P. F. Driever,
  • Berend Gagestein,
  • Elise Dusseldorp,
  • Marco van Eijk,
  • Uwe Grether,
  • Aletta M. R. van den Bosch,
  • Mignon de Goeij,
  • Annemieke J. M. Rozemuller,
  • Amy C. Harms,
  • Thomas Hankemeier,
  • Ludovic Collin,
  • Albert J. R. Heck,
  • Inge Huitinga,
  • Mario van der Stelt

摘要

Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures. These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination. Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression. Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.