Defining blood-induced microglia functions in neurodegeneration through multiomic profiling

Akassoglou and colleagues provide a single-cell RNA sequencing and phosphoprotein analysis of the responses of central nervous system microglia and macrophages to blood proteins including activated complement and fibrin. Their findings point to potential therapeutic targeting of microglia activation by immune and vascular signals. Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

Automated summary

Akassoglou and colleagues used single-cell RNA sequencing and phosphoprotein analysis to study the responses of CNS microglia and macrophages to blood proteins. They found that microglia activation by immune and vascular signals could be potential therapeutic targets. It is still largely unknown how blood proteins polarize innate immune cells.