Nencki Institute of Experimental Biology, Warsaw, Poland
NEW INSIGHTS OF THE ROLES OF MICROGLIA IN NEUROINFLAMMATION, DEPRESSION AND AGING BRAIN – ENLIGHTENMENTS FROM SINGLE-CELL OMICS##ABSTRACT##Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment and adapt a context-specific phenotype. Recent advances in transcriptomics and single-cell technologies allow studying microglia at high resolution and demonstrate the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies. A precise definition of microglia states is essential to design future immune-modulating therapies. Transcriptomics studies revealed both heterogeneity and plasticity of microglia and myeloid cells in stroke-neuroinflammation. Depression-like behavior is associated with a distinct microglia activation and triggers specific changes in gene expression in experimental mice. The changes could be modulated by behavioral strategies. Survival of microglia in CNS depends on colony stimulating factor 1 receptor (CSF1R) signaling and CSF1R inhibitors depletes 99% of microglia in a few weeks. Microglia repopulate within 1 week upon cessation of treatment in adult mice as demonstrated by TMEM119 immunohistochemical staining and flow cytometry. We investigated the origin and functionality of repopulated microglia in young and old mouse brains using single-cell RNA sequencing (scRNA-seq), flow cytometry and immunohistochemistry. Interestingly, confocal and Scholl analysis of microglial cell body and branching revealed that repopulated cells display distinct morphology. Repopulated microglia originating by proliferation from precursor microglia reconstitute the functional clusters but vary in morphology and express higher levels of pro-inflammatory genes than controls. Intriguingly, in old mice more repopulated microglia persist as proliferating cells and do not reach mature microglia phenotype. The results highlight subtle differences in the repopulation of microglia in aged brains that might contribute to deterioration of its protective functions with aging.