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Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response
Molecular Brain ( IF 3.3 ) Pub Date : 2021-06-03 , DOI: 10.1186/s13041-021-00794-7
Lara Friess 1 , Mathilde Cheray 1 , Lily Keane 1 , Kathleen Grabert 1 , Bertrand Joseph 1
Affiliation  

Microglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction states. Hence, the identification of modulators of selective microglial transcriptomic signature, which have the potential to regulate unique microglial function has gained interest. Here, we report the identification of ATG7 (Autophagy-related 7) as a selective modulator of an NF-κB-dependent transcriptional program controlling the pro-inflammatory response of microglia. We also uncover that microglial Atg7-deficiency was associated with reduced microglia-mediated neurotoxicity, and thus a loss of biological function associated with the pro-inflammatory microglial reactive state. Further, we show that Atg7-deficiency in microglia did not impact on their ability to respond to alternative stimulus, such as one driving them towards an anti-inflammatory/tumor supportive phenotype. The identification of distinct regulators, such as Atg7, controlling specific microglial transcriptional programs could lead to developing novel therapeutic strategies aiming to manipulate selected microglial phenotypes, instead of the whole microglial population with is associated with several pitfalls.

中文翻译:

小胶质细胞中的 Atg7 缺乏导致与神经炎症反应受损相关的转录组谱改变

小胶质细胞是中枢神经系统的常驻免疫活性细胞,可以表现出一系列反应状态,从而在发育、成年期和疾病条件下表现出不同的生物学功能。据报道,不同的基因表达谱定义了这些小胶质细胞反应状态中的每一个。因此,具有调节独特小胶质细胞功能潜力的选择性小胶质细胞转录组特征调节剂的鉴定引起了人们的兴趣。在这里,我们报告了将 ATG7(自噬相关 7)鉴定为控制小胶质细胞促炎反应的 NF-κB 依赖性转录程序的选择性调节剂。我们还发现小胶质细胞 Atg7 缺乏与小胶质细胞介导的神经毒性降低有关,因此,与促炎性小胶质细胞反应状态相关的生物学功能丧失。此外,我们表明小胶质细胞中 Atg7 的缺乏不会影响它们对替代刺激做出反应的能力,例如将它们推向抗炎/肿瘤支持表型的刺激。控制特定小胶质细胞转录程序的不同调节因子(如 Atg7)的识别可能导致开发新的治疗策略,旨在操纵选定的小胶质细胞表型,而不是与几个陷阱相关的整个小胶质细胞群。
更新日期:2021-06-03
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