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ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice.

ABSTRACT: Microglia, resident myeloid immune cells of the central nervous system (CNS), actively shape the circuitry of the brain, maintain CNS homeostasis during the steady state and orchestrate immune responses upon CNS injury. Both canonical and non-canonical functions of the macroautophagy/autophagy-related protein ATG5 regulate myeloid cell survival and immune responses. Here, we report that loss of ATG5 in postnatal microglia does not perturb CNS tissue integrity, microglial cell survival, or immune activation. Learning task performances were unchanged in mutant mice. Furthermore, lack of ATG5 expression in microglia had no impact on the development of experimental autoimmune encephalomyelitis. These data indicate that, basal autophagy, identified to be essential for the survival and function of neuronal cells, is not required to maintain CNS homeostasis if absent in adult microglia and ATG5 expression is dispensable for the development of autoimmune neuroinflammation.Abbreviations Ag, antigen; APC, antigen presenting cell; ATG/Atg, autophagy-related; CD, cluster of differentiation; CNS, central nervous system; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; fl, floxed; LAP, LC3-associated phagocytosis; LC3, microtubule-associated protein 1 light chain 3; MFI, median fluorescence intensity; MHCII, major histocompatibility complex class II; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis.

SUBMITTER: Srimat Kandadai K

PROVIDER: S-EPMC8632310 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice.

Srimat Kandadai Keertana K Kotur Monika B MB Dokalis Nikolaos N Amrein Irmgard I Keller Christian W CW Münz Christian C Wolfer David D Prinz Marco M Lünemann Jan D JD

Autophagy 20210208 11

Microglia, resident myeloid immune cells of the central nervous system (CNS), actively shape the circuitry of the brain, maintain CNS homeostasis during the steady state and orchestrate immune responses upon CNS injury. Both canonical and non-canonical functions of the macroautophagy/autophagy-related protein ATG5 regulate myeloid cell survival and immune responses. Here, we report that loss of ATG5 in postnatal microglia does not perturb CNS tissue integrity, microglial cell survival, or immune ...[more]

PMID: 33522362

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Project description:BackgroundNeuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated with tumours and inflammatory diseases. However, the role of TRIM45 in SAE and the relationship between TRIM45 and microglial pyroptosis are unknown. In this study, we found that TRIM45 played an important role in regulating microglial pyroptosis and the molecular mechanism.MethodsSAE was induced by intraperitoneal injection of LPS in WT and AAV-shTRIM45 mice. BV2 cells were treated with LPS/ATP in vitro. Cognitive function was assessed by the Morris water maze. Nissl staining was used to evaluate histological and structural lesions. ELISA was used to dectect neuroinflammation. qPCR was used to detect the mRNA levels of inflammatory cytokines, NLRP3, and autophagy genes. Western blotting and immunofluorescence analysis were used to analyse the expression of the proteins. Changes in reactive oxygen species (ROS) in cells were observed by flow cytometry. Changes in mitochondrial membrane potential in BV2 cells were detected by JC-1 staining. Peripheral blood mononuclear cells were extracted from blood by density gradient centrifugation and then used for qPCR, western blotting and flow detection. To further explore the mechanism, we used the overexpression plasmids TRIM45 and Atg5 as well as siRNA-TRIM45 and siRNA-Atg5 to analyse the downstream pathway of NLRP3. The protein and mRNA levels of TRIM45 in peripheral blood mononuclear cells from sepsis patients were examined.ResultsKnocking down TRIM45 protected against neuronal damage and cognitive impairment in septic mice. TRIM45 knockdown inhibited microglial pyroptosis and the secretion of inflammatory cytokines in vivo and in vitro, which was mediated by NLRP3/Gsdmd-N activation. Overexpression of TRIM45 could activate NLRP3 and downstream proteins. Further examination showed that TRIM45 regulated the activation of NLRP3 by altering Atg5 and regulating autophagic flux. It was also found that overexpression and knockdown of TRIM45 affected the changes in ROS and mitochondrial membrane potential. Thus, knocking down TRIM45 could reduce microglial pyroptosis, the secretion of proinflammatory cytokines, and neuronal damage and improve cognitive function. In addition, the level of TRIM45 protein in septic patients was increased. There was a positive linear correlation between APACHE II score and TRIM45, between SOFA score and TRIM45. Compared to group GCS > 9, level of TRIM45 were increased in group GCS ≤ 8.ConclusionTRIM45 plays a key role in neuroinflammation caused by LPS, and the mechanism may involve TRIM45-mediated exacerbation of microglial pyroptosis via the Atg5/NLRP3 axis.

Dataset Information

ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice.

Publications

ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice.

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