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

by Selleckchem | Sep 04 2023

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.

Comments:

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis that can lead to delirium, coma, and long-term cognitive dysfunction. Recent research has provided insights into the underlying mechanisms of SAE, particularly involving microglia and complement activation.

Studies have examined hippocampal autopsy tissue from patients with sepsis and found evidence of microglial activation and C1q complement activation. Additionally, a murine model of polymicrobial sepsis demonstrated increased C1q-mediated synaptic pruning. Transcriptomic analysis of both hippocampal tissue and isolated microglia from septic mice revealed the involvement of the innate immune system, complement activation, and upregulation of lysosomal pathways. These findings suggest that the innate immune response, specifically microglia and complement activation, play a role in the development of SAE.

Further experiments utilized a specific C1q-blocking antibody, which was injected stereotactically into the hippocampus to prevent microglial engulfment of C1q-tagged synapses. This intervention successfully inhibited the synaptic pruning process. Another pharmacological approach involved using PLX5622, a CSF1-R inhibitor that targets microglia. Treatment with PLX5622 resulted in reduced C1q levels, a decrease in the number of C1q-tagged synapses, protection against neuronal damage and synapse loss, and improved neurocognitive outcomes.

Overall, the research suggests that complement-dependent synaptic pruning by microglia is a crucial mechanism in the development of neuronal defects during SAE. These findings provide potential therapeutic targets for mitigating the neurological complications associated with sepsis. However, it's important to note that the information provided here is based on a hypothetical study scenario and does not reflect the results of any specific published research.