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<p>Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in <i>Casp1</i>/<i>Casp4</i>-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS.</p>

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Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • Ruoqi Yu,
  • Brian M. Lozinski,
  • Ally Seifert,
  • Khanh Ta,
  • Stephanie Zandee,
  • Deepak K. Kaushik,
  • Jian Park,
  • Wendy Klement,
  • Sandra Larouche,
  • Sotirios Tsimikas,
  • Joseph L. Witztum,
  • Dorian B. McGavern,
  • Alexandre Prat,
  • Yifei Dong

摘要

Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in Casp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS.