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.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

“…Our study demonstrates that C1q was involved in the microglial elimination of synapses in the CA1 region after repeated sevoflurane anesthesia. We also found that C1q was primarily produced by microglia rather than astrocytes, which is in line with recent studies [ 52 – 54 ]. Hence, we suppressed C1q expression using the specific antibody ANX005, which decreased synapse loss and improved memory and learning ability.…”

Sepsis‐associated encephalopathy: Autophagy and miRNAs regulate microglial activation

“…Hyperactivation of microglia, which are innate immune cells, is a major player in neuroinflammation (Leng & Edison, 2021 ) and induces a variety of neuropathological disorders, such as SAE, Alzheimer's disease, spinal cord injury, Parkinson's disease and subarachnoid hemorrhage (Jiang et al., 2020 ; Leng & Edison, 2021 ; Liu et al., 2022 ; Shen et al., 2021 ; Tian et al., 2022 ). Classically activated (M1) microglia directly or indirectly induce neuropathological changes, such as astrocyte activation, brain endothelial damage, inflammation, synaptic dysfunction, neuronal damage and cell death (Chen et al., 2021 ; Karunia et al., 2021 ), through the release of proinflammatory factors, oxidative products, chemokines and complement factors (Yan et al., 2022 ; Ye et al., 2019 ), In SAE, microglia activate and subsequently phagocytose neurons, including those in the neuronal cytosol, synapses (Chung et al., 2023 ; Wu et al., 2023 ) and myelin sheaths, leading to structural or functional abnormalities in the brain (Jansen et al., 2022 ; Karunia et al., 2021 ), which can cause cognitive dysfunction and acute neurological deficits. Therefore, modulation of microglial activation and polarization, which tends to be beneficial, is important for improving the prognosis of a variety of inflammation‐associated neurological disorders, such as SAE.…”

Immunotherapy in the context of sepsis-induced immunological dysregulation

“…Macrophages polarize toward an M1 inflammatory phenotype and release large amounts of IL-1β, TNF-α, and IL-6 ( 61 – 63 ), while DCs mediate the activation of CD4 + T ( 64 ). This syndrome is also accompanied by an imbalance of redox reactions ( 65 , 66 ), neutrophil-endothelial cell adhesion ( 67 ), activation of the complement system ( 68 , 69 ), and the coagulation cascade ( 70 , 71 ). Additionally, intense complement activation (especially C3 and C5a) enhances vascular permeability, and increases the adhesiveness between leukocytes and vascular endothelial cells, further promoting the inflammatory response and damaging self-tissue organs ( 72 , 73 ).…”