Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.

多发性硬化症 (MS) 是由中枢神经系统 (CNS) 中的炎症和神经变性引起的年轻人无法治愈的进行性残疾的主要原因。小胶质细胞清除组织碎片的能力对于维持和恢复中枢神经系统稳态至关重要。这种能力随着年龄的增长而减弱，而且年龄与 MS 疾病进展密切相关，尽管其潜在机制仍然在很大程度上难以捉摸。在这里，我们证明了 MS 小鼠模型中 CNS 炎症的恢复取决于小胶质细胞清除组织碎片的能力。自噬调节因子Atg7 的小胶质细胞特异性缺失，但不是典型的巨自噬蛋白Ulk1，导致吞噬髓鞘的细胞内积累增加和进行性 MS 样疾病。这种损伤与先前与神经退行性疾病相关的小胶质细胞表型相关。此外，Atg7- 缺陷的小胶质细胞显示出与来自老年野生型小鼠的小胶质细胞显着的转录和功能相似性，这些小鼠也无法清除髓鞘并从疾病中恢复。相比之下，使用在植物和真菌中发现的二糖海藻糖诱导老年小鼠的自噬导致功能性髓鞘清除和疾病缓解。我们的结果表明，小胶质细胞中一种非典型的自噬形式负责髓鞘降解和清除，从而导致 MS 样疾病的恢复，并且促进这一过程具有治疗年龄相关神经炎症疾病的潜力。