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Updated: Jun 13, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy
Ha-Yeun Chung1,2, Jonathan Wickel1,2, Nina Hahn1,2
1Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena 07747, Germany.
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.
Insights
Sepsis-associated encephalopathy (SAE) involves microglia-mediated synaptic pruning, driven by complement C1q activation. Blocking C1q or targeting microglia improves neurocognitive outcomes in sepsis models.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis.
- SAE leads to delirium, coma, and persistent cognitive deficits.
- The underlying mechanisms of SAE, particularly neuronal damage, remain incompletely understood.
Purpose of the Study:
- To investigate the role of microglia and complement activation in SAE pathogenesis.
- To identify molecular pathways involved in neuronal and synaptic damage during SAE.
- To explore therapeutic strategies targeting microglial activation and complement pathways.
Main Methods:
- Analysis of human autopsy hippocampal tissue from sepsis patients.
- Utilized a murine polymicrobial sepsis model.
- Performed unbiased transcriptomics on hippocampal tissue and isolated microglia.
- Investigated C1q-mediated synaptic pruning and microglial engulfment.
- Administered C1q-blocking antibody and CSF1-R inhibitor (PLX5622).
Main Results:
- Identified microglia and C1q complement activation in SAE patient hippocampi.
- Observed increased C1q-mediated synaptic pruning in a murine sepsis model.
- Transcriptomics revealed innate immune system involvement, complement activation, and lysosomal pathway up-regulation.
- Demonstrated that C1q-blocking antibody prevented microglial engulfment of synapses.
- PLX5622 treatment reduced C1q, protected synapses, and improved neurocognitive function.
Conclusions:
- Complement-dependent synaptic pruning by microglia is a key mechanism in SAE.
- Targeting microglia or C1q offers a potential therapeutic approach for SAE.
- Understanding these pathways is crucial for mitigating long-term cognitive dysfunction post-sepsis.
