Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.
Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.
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DOI：
10.18632/aging.100805
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Venero JL
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文献类型：
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作者：
Kavanagh E;Burguillos MA;Carrillo-Jimenez A;Oliva-Martin MJ;Santiago M;Rodhe J;Joseph B;Venero JL
越来越多的证据表明，不同神经退行性疾病，特别是帕金森病 (PD) 的发病机制中存在持续的促炎性小胶质细胞激活。我们最近发现了 caspase-8 及其下游底物 caspase-3/7 在控制小胶质细胞激活和与多巴胺能细胞相关的神经毒性方面的全新且意想不到的作用。为了证明遗传证据，将带有 CASP8 floxed 等位基因的小鼠与在溶菌酶 2 基因控制下表达 Cre 的转基因品系杂交。对大脑小胶质细胞中 caspase-8 基因缺失的分析表明，在激活的小胶质细胞中效率很高，但在驻留的小胶质细胞中则不然。小鼠接受脂多糖（小胶质细胞活化的有效诱导剂）或 MPTP（促进特定多巴胺能细胞损伤和随后的反应性小胶质细胞增生）的攻击。在这两种模型中，CASP8 缺失似乎都不影响表达泛特异性小胶质细胞标记 Iba1 的小胶质细胞总数。相比之下，CD16/CD32 表达（一种小胶质细胞促炎标记物）被发现在 CASP8 缺失后受到负面影响。还发现其他促炎标记物的表达因脂多糖的反应而减少。重要的是，在 PD 的 MPTP 小鼠模型中，促炎性小胶质细胞激活的减少伴随着黑质纹状体多巴胺能系统的显着保护。
Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele of CASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.