Abstract
G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes CX3CR1, GPR34, GPR183, P2RY12, P2RY13, and ADGRG1. Expression of these microglial core genes was lost upon culture of isolated cells ex vivo but could be acquired by human induced pluripotent stem cell (iPSC)-derived microglial precursors transplanted into mouse brains. CXCR4 and PTGER4 were higher expressed in subcortical white matter compared to cortical grey matter microglia, and ADGRG1 was downregulated in microglia obtained from normal-appearing white and grey matter tissue of multiple sclerosis (MS) brains. Single-cell RNA sequencing of microglia from active lesions, obtained early during MS, revealed downregulation of homeostasis-associated GPCR genes and upregulation of CXCR4 expression in a small subset of MS-associated lesional microglia. Functional presence of low levels of CXCR4 on human microglia was confirmed using flow cytometry and transwell migration towards SDF-1. Microglia abundantly expressed the GPCR down-stream signaling mediator genes GNAI2 (αi2), GNAS (αs), and GNA13 (α13), the latter particularly in white matter. Drugs against several microglia GPCRs are available to target microglia in brain diseases. In conclusion, transcriptome profiling allowed us to identify expression of GPCRs that may contribute to brain (patho)physiology and have diagnostic and therapeutic potential in human microglia.
Highlights
Microglia are brain-resident phagocytic cells that contribute to brain homeostasis as well as disease (1, 2)
To explore the presence of G protein-coupled receptors (GPCRs) in microglia, we utilized the list of GPCRs not involved in olfaction, taste, light perception, and pheromone signaling as provided by the International Union of Basic and Clinical Pharmacology (IUPHAR)/British Pharmacological Society (BPS) Guide to Pharmacology (20)
To identify GPCR genes that are reliably expressed in human microglia, we first tested bulk RNA sequencing (RNAseq) expression data of homeostatic microglia from different vertebrate species we recently published (8)
Summary
Microglia are brain-resident phagocytic cells that contribute to brain homeostasis as well as disease (1, 2). Populating the central nervous system (CNS) during embryonic development, microglia persist for the rest of life through local self-renewal. As a consequence, they possess a unique transcriptional signature that emerged only recently from RNA sequencing (RNAseq) of purified primary cells (3). GPCRs control cell and tissue physiology by regulating signaling pathways via heterotrimeric G proteins, which modulate cellular levels of second messengers and, in turn, a wide array of functional activities in all types of cells (6). Exploring bulk and single cell RNAseq studies of microglia from mice and human, we here describe the expression of GPCR and G protein genes in relation to microglia homeostasis, location, health, and disease
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