C9orf72
中性粒细胞
神经炎症
CD80
髓样
小胶质细胞
细胞生物学
免疫学
生物
癌症研究
炎症
细胞毒性T细胞
CD40
体外
等位基因
三核苷酸重复扩增
基因
生物化学
作者
Francesco Limone,Alexander Benavides Couto,Jin‐Yuan Wang,Y Zhang,Blake McCourt,Christine Huang,Adina Minkin,Márton Jani,Sarah K. McNeer,James Keaney,Gaëlle Gillet,Rodrigo López-González,Wendy A. Goodman,Irena Kadiu,Kevin Eggan,Aaron Burberry
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2024-01-31
卷期号:16 (732)
标识
DOI:10.1126/scitranslmed.adg7895
摘要
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.
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