Оксидизированные фосфатидилхолины вызывают хроническое нейродегенерацию в мышиной модели прогрессивного множественного склероза через IL-1β сигнализацию.
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Yu Ruoqi, Lozinski Brian M, Seifert Ally, Ta Khanh, Zandee Stephanie, Kaushik Deepak K, Park Jian, Klement Wendy, Larouche Sandra, Tsimikas Sotirios, Witztum Joseph L, McGavern Dorian B, Prat Alexandre, Dong Yifei
Аннотация
Оригинал публикации
Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling.
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.