小柯机器人

美国雪松-西奈医疗中心Robert H. Baloh研究小组的最新研究揭示髓样细胞中C9orf72抑制STING诱导的炎症。该研究于2020年8月19日在线发表于国际学术期刊《自然》杂志上。

研究人员发现在小鼠中，仅髓样细胞丢失C9orf72就足以产生C9orf72全身性敲出动物中观察到的年龄依赖性淋巴样肥大和自身炎症。从C9orf72^-/-小鼠分离的树突状细胞具有显著的I型干扰素应答早期激活，而C9orf72^-/-髓样细胞对干扰素基因（STING）蛋白刺激物的激活剂选择性高反应，STING是响应细胞质DNA的先天免疫关键调节因子。在C9orf72^-/-髓样细胞中，自身溶酶体依赖的STING降解途径缺失，而抑制STING则阻断了C9orf72^-/-免疫细胞中过度激活的I型干扰素反应以及C9orf72^-/-小鼠的脾肿大和炎症。

此外，C9orf72一个或两个拷贝缺失的小鼠更容易患上实验性自身免疫性脑炎，这反映出C9--肌萎缩性侧索硬化症（ALS）/额颞叶痴呆（FTD）患者对自身免疫性疾病的敏感性。

最后，与散发性ALS/FTD患者的样品相比，C9-ALS/FTD患者血液来源的巨噬细胞、全血和脑组织均显示出I型干扰素表达升高。STING抑制剂可以抑制这种增强的干扰素反应。

总体而言，这些结果表明，C9-ALS/FTD患者的免疫表型发生了改变，这是由于C9orf72的减少无法抑制STING诱导I型干扰素介导的炎症反应。

据悉，ALS和FTD是神经退行性疾病，在临床表现、病理和遗传起源方面存在重叠。自身免疫性疾病在ALS和FTD中也都存在，但在流行病学观察中这种现象仍然无法解释。C9orf72基因中六核苷酸重复序列（GGGGCC）的扩增是家族性ALS和FTD（C9-ALS/FTD）的最常见病因，其导致包含重复序列的RNA和二肽积累，以及大脑和外周血细胞中C9orf72蛋白表达降低。

附：英文原文

Title: C9orf72 in myeloid cells suppresses STING-induced inflammation

Author: Madelyn E. McCauley, Jacqueline Gire ORourke, Alberto Yez, Janet L. Markman, Ritchie Ho, Xinchen Wang, Shuang Chen, Deepti Lall, Mengyao Jin, A. K. M. G. Muhammad, Shaughn Bell, Jesse Landeros, Viviana Valencia, Matthew Harms, Moshe Arditi, Caroline Jefferies, Robert H. Baloh

Issue&Volume: 2020-08-19

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1–3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4–6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72−/− mice show marked early activation of the type I interferon response, and C9orf72−/− myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein—a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72−/− myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72−/− immune cells as well as splenomegaly and inflammation in C9orf72−/− mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING. Studies of mice and humans suggest a role for loss of the C9orf72 protein in some neurodegenerative disorders: with reduced C9orf72 levels, there is more inflammation mediated by the STING protein in immune and brain cells.

DOI: 10.1038/s41586-020-2625-x

Source: https://www.nature.com/articles/s41586-020-2625-x

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