Conserved Transcriptional Signatures of Microglia in Health and Disease (P2-3.011)

Abstract

<h3>Objective:</h3> To determine signatures of microglia in humans and mice in the context of central nervous system (CNS) inflammation and homeostasis. <h3>Background:</h3> Single cell profiling of gene expression has illuminated the heterogeneity of immune cells and accessible phenotypes across organs and under a myriad of conditions. These efforts—typified by recent studies aiming to identify signatures of microglia—typically entail pre-enrichment of cell populations, even from distinct species, using a limited set of surface markers or morphological traits. This step introduces potential bias and subjectivity that may alter the gene expression states that are discerned. <h3>Design/Methods:</h3> We queried the NCBI GEO for datasets of single-cell transcription within CNS tissue from healthy subjects, multiple sclerosis (MS) patients, and mice afflicted with experimental autoimmune encephalomyelitis (EAE). In total, this yielded data on over 135,000 human cells—encompassing a spectrum of lesion chronicity in patients with progressive and relapsing-remitting MS—and 12,000 murine cells. Datasets were pre-processed for quality control and harmonized according to species prior to cross-species integration. We developed classifier models of microglia using logistic regression and support vector machine frameworks. <h3>Results:</h3> Unexpectedly, markers closely linked in the literature to microglia, including Iba-1, were found to be expressed in non-microglial myeloid cells. Other markers previously ascribed to microglia in one species, such as Hexb, failed to represent useful markers in the other species. We identified intra- and inter-species signatures of microglia using machine-learning methods that form the basis of future studies. <h3>Conclusions:</h3> Whole-brain, single-cell gene expression data, unencumbered by bias introduced by prior cell enrichment, enable identification of transcriptional signatures of cell types across species. Signatures of microglia during CNS inflammation identify potentially targetable pathways to understand their role in disease and limit tissue injury. <b>Disclosure:</b> The institution of an immediate family member of Dr. Salinas has received research support from Veterans Health Administration. Navid Manouchehri has nothing to disclose. Rehana Hussain has nothing to disclose. Dr. Stuve has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Stuve has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Stuve has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Genentech. Dr. Stuve has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Stuve has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Stuve has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Stuve has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for VYNE. Dr. Stuve has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Therapeutic Advances in Neurological Diseases. Dr. Stuve has received research support from US Department of Veterans Affairs. Dr. Stuve has received research support from National Multiple Sclerosis Society (US). Dr. Stuve has received research support from Exalys. Dr. Stuve has received research support from Merck KGaA.