Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination.
Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination.
复制标题
瓜氨酸髓鞘诱导小胶质细胞TNFα并抑制脱髓鞘铜腙模型中的内源性修复
DOI：
10.1186/s12974-021-02360-3
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发表时间：
2021-12-27
影响因子：
9.3
通讯作者：
Howe CL
中科院分区：
文献类型：
--
作者：
Standiford MM;Grund EM;Howe CL
小胶质细胞是中枢神经系统的主要吞噬细胞，负责清除脱髓鞘后受损的髓鞘。先前探索髓鞘吞噬作用对小胶质细胞活化的后果的研究忽略了髓鞘碎片上存在的生化修饰。这种修饰，包括瓜氨酸，在多发性硬化病变的炎症环境中增加。通过与钙依赖性肽基精氨酸脱亚胺酶PAD 2孵育，将通过超离心分离的小鼠皮质髓鞘离体瓜氨酸化。脱髓鞘由6周的cuprizone（0.3%）治疗诱导，并通过恢复正常饮食启动自发修复。在恢复正常食物时，将瓜氨酸化或未修饰的髓鞘注射到扣带束上方的初级运动皮层中，并通过测量3周后皮层中髓鞘碱性蛋白阳性纤维的表面积来评估对髓鞘再生的影响。通过测量细胞因子释放、评估小胶质细胞活化的流式细胞术标记物和转录变化的RNAseq分析来表征小胶质细胞对髓鞘的反应。瓜氨酸化髓鞘诱导了一种独特的小胶质细胞反应，其特征在于体外和体内肿瘤坏死因子α（TNFα）的产生增加。这种反应不是由未修饰的髓磷脂诱导的。将瓜氨酸化的髓磷脂注射到铜腙脱髓鞘小鼠的皮质中，而不是未修饰的髓磷脂，显著抑制了自发性髓鞘再生。抗体介导的TNFα中和阻断了这种作用，并将髓鞘再生恢复到正常水平。这些发现强调了翻译后修饰（如瓜氨酸）在确定脱髓鞘期间响应髓鞘的小胶质细胞活化中的作用。瓜氨酸化髓鞘诱导的内源性修复的抑制作用以及中和TNFα逆转该作用可能对炎性脱髓鞘疾病患者的治疗方法有意义。在线版本包含补充材料，可通过10.1186/s12974-021-02360-3获得。
Microglia are the primary phagocytes of the central nervous system and are responsible for removing damaged myelin following demyelination. Previous investigations exploring the consequences of myelin phagocytosis on microglial activation overlooked the biochemical modifications present on myelin debris. Such modifications, including citrullination, are increased within the inflammatory environment of multiple sclerosis lesions. Mouse cortical myelin isolated by ultracentrifugation was citrullinated ex vivo by incubation with the calcium-dependent peptidyl arginine deiminase PAD2. Demyelination was induced by 6 weeks of cuprizone (0.3%) treatment and spontaneous repair was initiated by reversion to normal chow. Citrullinated or unmodified myelin was injected into the primary motor cortex above the cingulum bundle at the time of reversion to normal chow and the consequent impact on remyelination was assessed by measuring the surface area of myelin basic protein-positive fibers in the cortex 3 weeks later. Microglial responses to myelin were characterized by measuring cytokine release, assessing flow cytometric markers of microglial activation, and RNAseq profiling of transcriptional changes. Citrullinated myelin induced a unique microglial response marked by increased tumor necrosis factor α (TNFα) production both in vitro and in vivo. This response was not induced by unmodified myelin. Injection of citrullinated myelin but not unmodified myelin into the cortex of cuprizone-demyelinated mice significantly inhibited spontaneous remyelination. Antibody-mediated neutralization of TNFα blocked this effect and restored remyelination to normal levels. These findings highlight the role of post-translation modifications such as citrullination in the determination of microglial activation in response to myelin during demyelination. The inhibition of endogenous repair induced by citrullinated myelin and the reversal of this effect by neutralization of TNFα may have implications for therapeutic approaches to patients with inflammatory demyelinating disorders. The online version contains supplementary material available at 10.1186/s12974-021-02360-3.
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影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
14.5
作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
Bethea, John R.
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
影响因子：
12.4
作者：
Bonora, M.;De Marchi, E.;Pinton, P.
通讯作者：
Pinton, P.
影响因子：
2.2
作者：
Kawaguchi, Hoshimi;Matsumoto, Isao;Sumida, Takayuki
通讯作者：
Sumida, Takayuki