Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy
Ha‐Yeun Chung, Jonathan Wickel, Nina Hahn, Nils Mein, Meike Schwarzbrunn, Philipp Koch, Mihai Ceangă, Holger Haselmann, Carolin Baade‐Büttner, Nikolai von Stackelberg, Nina Hempel, Lars Schmidl, Marco Groth, Nico Andreas, Juliane Götze, Sina M. Coldewey, Michael Bauer, Christian Mawrin, Justina Dargvainiene, Frank Leypoldt, Stephan Steinke, Zhao‐Qi Wang, Michael Hust, Christian Geis
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.