Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures

Abstract

Microglia are specialized parenchymal‐resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are thought to worsen CNS diseases; nevertheless, their impact during neuroinflammatory processes remains largely obscure. Here, using a combination of single‐cell RNA sequencing and multicolour flow cytometry, we comprehensively profile microglia in the brain of lipopolysaccharide (LPS)‐injected mice. By excluding the contribution of other immune CNS‐resident and peripheral cells, we show that microglia isolated from LPS‐injected mice display a global downregulation of their homeostatic signature together with an upregulation of inflammatory genes. Notably, we identify distinct microglial activated profiles under inflammatory conditions, which greatly differ from neurodegenerative disease‐associated profiles. These results provide insights into microglial heterogeneity and establish a resource for the identification of specific phenotypes in CNS disorders, such as neuroinflammatory and neurodegenerative diseases.

Transcriptional profiling of microglia; current state of the art and future perspectives

“…Also, a large overlap between cells and nuclei was observed both after PBS and LPS stimulation (Figure b). Upon LPS stimulation, microglia shift from a homeostatic to an activated state resulting in an activated microglia subpopulation (Sousa et al, ). To confirm the induction of a subset of activated microglia, we determined the expression of homeostatic and activated microglia marker genes reported previously (Keren‐Shaul et al, ; Sousa et al, ).…”

NG2 glia are required for maintaining microglia homeostatic state

“…Microglia play vital roles in brain health and diseases. Depending on their cellular state, microglia exert distinct functions in different disease contexts (Sousa et al, ) and even in different stages of the same disease (Hamelin et al, ; Keren‐Shaul et al, ). Understanding the mechanisms of the transition between different microglia cellular states is essential for developing therapeutic approaches against neurodegenerative diseases.…”

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

“…They first emerge during the first postnatal week, peaking at P5 and gradually decreasing as animals age, being barely detectable in the healthy adult CNS (33-35, 42, 80, 81) to increase again in aging or disease (33,73,81,85,89). Importantly, none of the studies that have investigated induction of inflammation by means of lipopolysaccharide, poly(I:C), or other immune challenges could recapitulate the robust CD11c+ signature found in steady state and disease and injury contexts (86,88,90,124,155,156). Below, we present factors that participate in controlling the induction of this population (Figure 4).…”