A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72 -deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72 -mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72 -deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72 -deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72 -deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.

中文翻译：

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C9orf72 的骨髓和淋巴表达调节小鼠 IL-17A 信号传导

发生突变C9ORF72是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的最常见原因。 ALS 或 FTD 患者通常会在神经系统症状出现之前或同时出现自身免疫和炎症，但其潜在机制尚不清楚。在这里，我们淘汰了小鼠C9orf72通过条件诱变在七个造血祖细胞室中发现骨髓谱系C9orf72防止脾肿大、耐受性丧失和过早死亡。此外，我们证明了C9orf72在淋巴细胞中发挥作用，防止白细胞介素 17A (IL-17A) 产生和中性粒细胞增多。质谱流式细胞术发现共刺激分子 CD80 的早期和持续升高C9orf72-小鼠巨噬细胞、单核细胞和小胶质细胞缺陷。在患有以下疾病的患者的人脊髓小胶质细胞中也观察到 CD80 的富集。C9ORF72介导的 ALS 与非 ALS 对照相比。小鼠脊髓、脑皮层和脾脏的单细胞 RNA 测序表明，与抗原加工和呈递以及抗病毒免疫相关的基因模块的协调诱导C9orf72-内皮细胞、小胶质细胞和巨噬细胞缺陷。从机制上讲，C9ORF72 响应 Toll 样受体激动剂、干扰素-γ 和 IL-17A，抑制 CD80 向细胞表面的运输。删除伊尔17a在C9orf72-缺陷小鼠阻止了脊髓中 CD80 的富集、中性粒细胞减少和肠道 17 型辅助 T 细胞减少。最后，IL-17A 中和抗体的全身给药增强了运动表现并抑制了神经炎症。C9orf72- 缺陷小鼠。总而言之，我们表明C9orf72协调骨髓共刺激效力，并为 IL-17A 作为 ALS 或 FTD 相关神经炎症的治疗靶点提供支持。