Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.

中文翻译：

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硬脂酰辅酶A去饱和酶-1损害大脑中巨噬细胞和小胶质细胞的修复特性

髓鞘再生失败是脱髓鞘疾病（例如多发性硬化症）进行性发展的基础。巨噬细胞和小胶质细胞在脱髓鞘病变的形成和修复中至关重要。在这里，我们发现髓磷脂的摄取暂时使这些吞噬细胞偏向于解决疾病的表型，而髓磷脂的持续细胞内积累则诱导了病变促进的表型。这种表型转变是由硬脂酰辅酶A去饱和酶-1 (SCD1) 控制的，SCD1 是一种负责饱和脂肪酸去饱和的酶。SCD1 产生的单不饱和脂肪酸降低了胆固醇外流转运蛋白 ABCA1 的表面丰度，进而促进脂质积累并诱导炎症吞噬细胞表型。Scd1 的药理抑制或吞噬细胞特异性缺陷加速了离体和体内的髓鞘再生。这些发现将 SCD1 确定为促进髓鞘再生的新治疗靶点。