A sexually dimorphic role for complement protein C1q in modulating microglial inflammation 9366

Abstract Description Human neurodegenerative disease incidence, clinical manifestation, and pathogenesis exhibit well established sex differences, and in parallel, a strong link to microglial gene expression. Although RNA-sequencing studies highlight striking differences between male versus female microglia, mechanistic understanding of how male versus female microglia modulate inflammation is lacking. Complement protein C1q increases 300-fold in aging and neurodegeneration, and has been identified as a regulator of microglial inflammation. Here, we expand on this by investigating whether C1q similarly influences human induced pluripotent stem cell (hiPSC)-derived microglia from 3 male and 3 female donors. Strikingly, we report that C1q polarizes male microglia to an inflammatory state but does not affect female microglia. Because microglia are the primary producers of C1q in the brain, we tested the hypothesis that male but not female microglia use autocrine C1q to self-regulate inflammation. Indeed, we found that blockade of autocrine C1q using a C1q neutralizing antibody attenuates LPS-induced inflammation in male microglia, but amplifies inflammation in female microglia. These data identify a sexually dimorphic role for complement protein C1q in regulating microglial state. Future work will determine a mechanism for this differential function by probing recently identified C1q receptors and ultimately will inform sex-dependent therapeutic development for many neurodegenerative disorders. Topic Categories Neuroimmunology (NEUR)