Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss.
Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss.
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DOI：
10.1186/s13024-017-0210-z
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发表时间：
2017-09-18
影响因子：
15.1
通讯作者：
Tenner AJ
中科院分区：
文献类型：
--
作者：
Hernandez MX;Jiang S;Cole TA;Chu SH;Fonseca MI;Fang MJ;Hohsfield LA;Torres MD;Green KN;Wetsel RA;Mortazavi A;Tenner AJ
药理学抑制C5 aR 1，补体激活促炎片段C5 a的受体，抑制阿尔茨海默病（AD）小鼠模型的病理和认知缺陷。为了验证拮抗剂的作用特异性地通过C5 aR 1抑制，产生缺乏C5 aR 1的小鼠并在行为和病理学方面进行比较。此外，由于C5 aR 1主要在髓系细胞上表达，并且仅在较小程度上在脑中的内皮细胞和神经元上表达，因此在所有基因型中比较了从多个年龄的成人脑中分离的小胶质细胞中的基因表达。将C5 aR 1敲除小鼠与Arctic AD小鼠模型杂交，并在海马依赖性记忆任务中表征病理学和行为表现。将CX 3CR 1GFP和CCR 2 RFP报告基因小鼠与C5 aR 1足够和敲除的野生型和北极小鼠交配，以能够分选从2、5、7和10月龄的成年脑中分离的小胶质细胞（GFP阳性，RFP阴性），然后进行RNA-seq分析。缺乏C5 aR 1可以防止10个月时的行为缺陷，尽管淀粉样斑块负荷没有改变。免疫组织化学分析显示，在有或没有C5 aR 1的北极脑中，斑块附近没有CCR 2+单核细胞/巨噬细胞。从浸润的单核细胞（GFP和RFP阳性）中分选小胶质细胞用于转录组分析。RNA-seq分析将炎症相关基因鉴定为差异表达，其中北极小鼠中的表达相对于野生型增加，而北极/C5 aR 1 KO中的表达相对于北极降低。此外，相对于野生型，北极小鼠中的吞噬体-溶酶体基因表达增加，但在北极/C5 aR 1 KO小鼠中进一步增加。在10个月大的北极小鼠的海马体中观察到神经元复杂性的降低，这与行为缺陷相关，这两只小鼠都在北极/C5 aR 1 KO中获救。这些数据与在不存在C5 aR 1信号传导的情况下的小胶质细胞极化一致，反映了炎性基因的诱导减少和降解/清除途径的增强，这伴随着CA 1神经元复杂性和海马依赖性认知功能的保留。这些结果提供了小胶质细胞反应和认知能力丧失之间的联系，并结合先前抑制C5 aR 1信号传导的药理学方法，支持该受体作为人类AD新治疗靶点的潜力。本文的在线版本（10.1186/s13024-017-0210-z）包含补充材料，可供授权用户使用。
Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes. C5aR1 knock out mice were crossed to the Arctic AD mouse model, and characterized for pathology and for behavior performance in a hippocampal dependent memory task. CX3CR1GFP and CCR2RFP reporter mice were bred to C5aR1 sufficient and knockout wild type and Arctic mice to enable sorting of microglia (GFP-positive, RFP-negative) isolated from adult brain at 2, 5, 7 and 10 months of age followed by RNA-seq analysis. A lack of C5aR1 prevented behavior deficits at 10 months, although amyloid plaque load was not altered. Immunohistochemical analysis showed no CCR2+ monocytes/macrophages near the plaques in the Arctic brain with or without C5aR1. Microglia were sorted from infiltrating monocytes (GFP and RFP-positive) for transcriptome analysis. RNA-seq analysis identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wild type and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal gene expression was increased in the Arctic mice relative to wild type but further increased in the Arctic/C5aR1KO mice. A decrease in neuronal complexity was seen in hippocampus of 10 month old Arctic mice at the time that correlates with the behavior deficit, both of which were rescued in the Arctic/C5aR1KO. These data are consistent with microglial polarization in the absence of C5aR1 signaling reflecting decreased induction of inflammatory genes and enhancement of degradation/clearance pathways, which is accompanied by preservation of CA1 neuronal complexity and hippocampal dependent cognitive function. These results provide links between microglial responses and loss of cognitive performance and, combined with the previous pharmacological approach to inhibit C5aR1 signaling, support the potential of this receptor as a novel therapeutic target for AD in humans. The online version of this article (10.1186/s13024-017-0210-z) contains supplementary material, which is available to authorized users.
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影响因子：
9.3
作者：
Giunta B;Fernandez F;Nikolic WV;Obregon D;Rrapo E;Town T;Tan J
通讯作者：
Tan J
DOI：
10.4049/jimmunol.1202339
发表时间：
2012-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abe T;Hosur KB;Hajishengallis E;Reis ES;Ricklin D;Lambris JD;Hajishengallis G
通讯作者：
Hajishengallis G
影响因子：
9.3
作者：
Cribbs DH;Berchtold NC;Perreau V;Coleman PD;Rogers J;Tenner AJ;Cotman CW
通讯作者：
Cotman CW
影响因子：
5.3
作者：
Afagh, A;Cummings, BJ;Tenner, AJ
通讯作者：
Tenner, AJ
影响因子：
9.3
作者：
Fonseca, Maria I.;Chu, Shu-Hui;Tenner, Andrea J.
通讯作者：
Tenner, Andrea J.