Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation
Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation
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DOI：
10.1038/s41590-020-0661-1
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发表时间：
2020-04-20
影响因子：
30.5
通讯作者：
Mildner, Alexander
中科院分区：
文献类型：
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作者：
Giladi, Amir;Wagner, Lisa Katharina;Mildner, Alexander
Mildner和他的同事在实验诱导的自身免疫性脑脊髓炎小鼠的中枢神经系统中表征了两种具有致病潜力的单核细胞亚群(Cxcl10(+)和Saa3(+))，并表明这些致病细胞不是来自Ly6C(+)单核细胞，而是来自早期的髓系细胞前体。多发性硬化症(MS)的特征是病理炎症，这是由于淋巴和髓系免疫细胞从血液中重新聚集到大脑中造成的。由于亚群的异质性，确定各种细胞亚群在MS急性期和慢性期的功能作用一直是具有挑战性的。在这里，我们使用指数和转录单细胞分类来表征实验诱导的自身免疫性脑脊髓炎小鼠的单核巨噬细胞从外周渗透到中枢神经系统的特征，这是一种MS模型。我们在急性和慢性疾病阶段确定了8个单核细胞和3个树突状细胞亚群，在这些亚群中定义的转录程序指向不同的功能。单核细胞特异性细胞消融发现具有致病潜能的Cxcl10(+)和Saa3(+)单核细胞亚群。不同单核细胞和前体细胞亚群的移植实验表明，这些Cxcl10(+)和Saa3(+)致病细胞不是来自Ly6C(+)单核细胞，而是来自早期髓系祖细胞。这些结果表明，阻断特异性致病单核细胞亚群，包括Cxcl10(+)和Saa3(+)单核细胞，可用于靶向治疗干预。
Mildner and colleagues characterize two subsets (Cxcl10(+) and Saa3(+)) of monocytes with pathogenic potential in the central nervous system of mice with experimentally induced autoimmune encephalomyelitis and show these pathogenic cells are not derived from Ly6C(+) monocytes, but from early myeloid cell progenitors.Multiple sclerosis (MS) is characterized by pathological inflammation that results from the recruitment of lymphoid and myeloid immune cells from the blood into the brain. Due to subset heterogeneity, defining the functional roles of the various cell subsets in acute and chronic stages of MS has been challenging. Here, we used index and transcriptional single-cell sorting to characterize the mononuclear phagocytes that infiltrate the central nervous system from the periphery in mice with experimentally induced autoimmune encephalomyelitis, a model of MS. We identified eight monocyte and three dendritic cell subsets at acute and chronic disease stages in which the defined transcriptional programs pointed toward distinct functions. Monocyte-specific cell ablation identified Cxcl10(+) and Saa3(+) monocytic subsets with a pathogenic potential. Transfer experiments with different monocyte and precursor subsets indicated that these Cxcl10(+) and Saa3(+) pathogenic cells were not derived from Ly6C(+) monocytes but from early myeloid cell progenitors. These results suggest that blocking specific pathogenic monocytic subsets, including Cxcl10(+) and Saa3(+) monocytes, could be used for targeted therapeutic interventions.