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Single cell RNA sequencing of murine bone marrow derived macrophages and adipose tissue macrophages from lean and obese mice

ABSTRACT: Macrophages are key to innate immunity and tissue homeostasis. Plasticity of macrophages allows rapid and highly orchestrated responses to various pathogenic and physiological challenges. Capturing the dynamic intracellular programs employed by macrophages during encounters with various stimuli presents a demanding technical challenge, and failures to fully characterize some of these responses has stalled development of disease-specific therapy. Powered by single-cell RNA sequencing (scRNA-seq), we expanded current t-distributed stochastic neighbor embedding (t-SNE) single-cell transcriptome algorithms and established a novel platform, MacSpectrum (macspec.github.io), with newly generated indexes (Macrophage Polarization Index, MPI and Macrophage Maturation Index, MMI) that allow not only macrophage subpopulation characterization under various conditions but also disease-specific signature gene set identification. Our MacSpectrum model will provide a comprehensive system to annotate macrophage function and dissect their diversified programs under sophisticated conditions in vivo, which represents a major challenge in macrophage biology. Single cell RNA sequeicing profiles of 6979 M0 BMDMs , 4736 M1 BMDMs, 6391 M2 BMDMs, 1710 lean ATMs, and 1758 obese ATMs were generated.

ORGANISM(S): Mus musculus

PROVIDER: GSE117176 | GEO | 2019/04/24

REPOSITORIES: GEO

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Project description:Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions. F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1α-/- mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production. Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity. Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity.

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Single cell RNA sequencing of murine bone marrow derived macrophages and adipose tissue macrophages from lean and obese mice

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