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Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

ABSTRACT: Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE.

SUBMITTER: Chung HY

PROVIDER: S-EPMC10219600 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

Chung Ha-Yeun HY Wickel Jonathan J Hahn Nina N Mein Nils N Schwarzbrunn Meike M Koch Philipp P Ceanga Mihai M Haselmann Holger H Baade-Büttner Carolin C von Stackelberg Nikolai N Hempel Nina N Schmidl Lars L Groth Marco M Andreas Nico N Götze Juliane J Coldewey Sina M SM Bauer Michael M Mawrin Christian C Dargvainiene Justina J Leypoldt Frank F Steinke Stephan S Wang Zhao-Qi ZQ Hust Michael M Geis Christian C

Science advances 20230526 21

Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement a ...[more]

PMID: 37235660

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Project description:BackgroundSepsis-associated encephalopathy (SAE) is characterized by the activation of inflammatory cascades, in which microglia play a key role. The activation of Recombinant Sirtuin 3 (SIRT3) was shown to significantly reduce the susceptibility of microglia to inflammatory stress. The purpose of this study is to determine whether miRNA-494 can regulate the activation and oxidative stress of SAE microglia through SIRT3.MethodsAn SAE rat model was established, and the expression of Ionized calcium bindingadaptor molecule-1 (Iba-1) in rat brain tissue was detected by immunohistochemistry. Enzyme-linked immuno sorbent assay was performed to detect the expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in brain tissue. Real time quantitative PCR was performed to detect the relative expression of SIRT3 and related miRNAs, while Western blot was used to detect the protein expression of SIRT3. Rat microglia cells were cultured in vitro. After miRNA-494 was transfected, the expression of TNF-α and IL-6 was detected. Western blot was used to detect the protein expression of SIRT3 and Iba-1 in microglia.ResultsThe results showed that the expression of Iba-1 in the brain tissue of the SAE model group increased, and the expression of inflammatory factors TNF-α and IL-6 increased significantly (P<0.01). The expression of SIRT3 protein and mRNA in the brain tissue of the SAE model group also significantly increased (P<0.05). The relative expression of miRNA-494 in the SAE model group was significantly lower than that in the control group (P<0.01). After miRNA-494 was transfected into microglia, cells were treated with lipopolysaccharide. In the miRNA transfection group, the expression levels of TNF-α and IL-6 were significantly lower than those in the negative control (NC) group (P<0.01), and the protein expression levels of Iba-1 and SIRT3 were also significantly lower than those in the NC (P<0.01).ConclusionsMiRNA-494 may further regulate the activation of microglia in SAE by regulating mitochondrial function, providing basic research data for the development of new SAE treatment methods.

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Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

Publications

Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

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