Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response

Abstract

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.

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“…The ATG7 gene encodes an E1-like activating enzyme implicated in the regulation of organismal mitophagy ( Barrientos-Riosalido et al, 2023 ). Studies have shown that silencing ATG7 expression can slow the proinflammatory response of microglia, thereby slowing the progression of inflammation-mediated neurotoxicity during PD ( Burguillos et al, 2011 ; Friess et al, 2021 ). FADS2 is a fatty acid desaturase (FADS) gene family member.…”

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“…For instance, microglial Agt5 knockdown was sufficient to trigger M1 microglial polarization, while upregulation of autophagy promoted microglial polarization toward the M2 phenotype [ 22 ]. Microglial Atg7 deficiency was associated with reduced microglia-mediated neurotoxicity resulting in impaired microglial proinflammatory response [ 56 ]. In the animal studies, microglial autophagy is important for refining synapses during development, and defects cause autism spectrum disorder-like behavior [ 23 ].…”