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Intrinsic DNA damage repair deficiency results in progressive microglia loss and replacement
Glia ( IF 5.4 ) Pub Date : 2020-10-17 , DOI: 10.1002/glia.23925 Xiaoming Zhang 1 , Yang Heng 1 , Susanne M Kooistra 1 , Hilmar R J van Weering 1 , Maaike L Brummer 1 , Emma Gerrits 1 , Evelyn M Wesseling 1 , Nieske Brouwer 1 , Tjalling W Nijboer 1 , Marissa L Dubbelaar 1 , Erik W G M Boddeke 1, 2 , Bart J L Eggen 1
Glia ( IF 5.4 ) Pub Date : 2020-10-17 , DOI: 10.1002/glia.23925 Xiaoming Zhang 1 , Yang Heng 1 , Susanne M Kooistra 1 , Hilmar R J van Weering 1 , Maaike L Brummer 1 , Emma Gerrits 1 , Evelyn M Wesseling 1 , Nieske Brouwer 1 , Tjalling W Nijboer 1 , Marissa L Dubbelaar 1 , Erik W G M Boddeke 1, 2 , Bart J L Eggen 1
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The DNA excision repair protein Ercc1 is important for nucleotide excision, double strand DNA break, and interstrand DNA crosslink repair. In constitutive Ercc1‐knockout mice, microglia display increased phagocytosis, proliferation and an enhanced responsiveness to lipopolysaccharide (LPS)‐induced peripheral inflammation. However, the intrinsic effects of Ercc1‐deficiency on microglia are unclear. In this study, Ercc1 was specifically deleted from Cx3cr1‐expressing cells and changes in microglia morphology and immune responses at different times after deletion were determined. Microglia numbers were reduced with approximately 50% at 2–12 months after Ercc1 deletion. Larger and more ramified microglia were observed following Ercc1 deletion both in vivo and in organotypic hippocampal slice cultures. Ercc1‐deficient microglia were progressively lost, and during this period, microglia proliferation was transiently increased. Ercc1‐deficient microglia were gradually replaced by nondeficient microglia carrying a functional Ercc1 allele. In contrast to constitutive Ercc1‐deficient mice, microglia‐specific deletion of Ercc1 did not induce microglia activation or increase their responsiveness to a systemic LPS challenge. Gene expression analysis suggested that Ercc1 deletion in microglia induced a transient aging signature, which was different from a priming or disease‐associated microglia gene expression profile.
中文翻译：
内在 DNA 损伤修复缺陷导致小胶质细胞进行性丢失和替代
DNA 切除修复蛋白 Ercc1 对于核苷酸切除、双链 DNA 断裂和链间 DNA 交联修复非常重要。在Ercc1基因敲除小鼠中，小胶质细胞的吞噬作用和增殖能力增强，并且对脂多糖 (LPS) 诱导的外周炎症的反应性增强。然而， Ercc1缺陷对小胶质细胞的内在影响尚不清楚。在这项研究中， Ercc1被特意从表达Cx3cr1的细胞中删除，并测定了删除后不同时间小胶质细胞形态和免疫反应的变化。 Ercc1删除后 2-12 个月，小胶质细胞数量减少约 50%。在体内和器官型海马切片培养物中， Ercc1缺失后观察到更大、更分枝的小胶质细胞。 Ercc1缺陷的小胶质细胞逐渐消失，在此期间，小胶质细胞增殖短暂增加。 Ercc1缺陷型小胶质细胞逐渐被携带功能性Ercc1等位基因的无缺陷小胶质细胞所取代。与结构性Ercc1缺陷小鼠相比，小胶质细胞特异性删除Ercc1不会诱导小胶质细胞激活或增加其对全身 LPS 攻击的反应性。基因表达分析表明，小胶质细胞中的Ercc1缺失会诱导短暂的衰老特征，这与启动或疾病相关的小胶质细胞基因表达谱不同。
更新日期：2020-10-17
中文翻译：
内在 DNA 损伤修复缺陷导致小胶质细胞进行性丢失和替代
DNA 切除修复蛋白 Ercc1 对于核苷酸切除、双链 DNA 断裂和链间 DNA 交联修复非常重要。在Ercc1基因敲除小鼠中，小胶质细胞的吞噬作用和增殖能力增强，并且对脂多糖 (LPS) 诱导的外周炎症的反应性增强。然而， Ercc1缺陷对小胶质细胞的内在影响尚不清楚。在这项研究中， Ercc1被特意从表达Cx3cr1的细胞中删除，并测定了删除后不同时间小胶质细胞形态和免疫反应的变化。 Ercc1删除后 2-12 个月，小胶质细胞数量减少约 50%。在体内和器官型海马切片培养物中， Ercc1缺失后观察到更大、更分枝的小胶质细胞。 Ercc1缺陷的小胶质细胞逐渐消失，在此期间，小胶质细胞增殖短暂增加。 Ercc1缺陷型小胶质细胞逐渐被携带功能性Ercc1等位基因的无缺陷小胶质细胞所取代。与结构性Ercc1缺陷小鼠相比，小胶质细胞特异性删除Ercc1不会诱导小胶质细胞激活或增加其对全身 LPS 攻击的反应性。基因表达分析表明，小胶质细胞中的Ercc1缺失会诱导短暂的衰老特征，这与启动或疾病相关的小胶质细胞基因表达谱不同。
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