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Front Immunol. 2019 Dec 11;10:2887. doi: 10.3389/fimmu.2019.02887. eCollection 2019.

Meta-Analysis of in vitro-Differentiated Macrophages Identifies Transcriptomic Signatures That Classify Disease Macrophages in vivo.

Author information

1
Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
2
Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
3
Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom.
4
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
5
Computational Biology, Target Sciences, GlaxoSmithKline, Stevenage, United Kingdom.
6
Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany.

Abstract

Macrophages are heterogeneous leukocytes regulated in a tissue- and disease-specific context. While in vitro macrophage models have been used to study diseases empirically, a systematic analysis of the transcriptome thereof is lacking. Here, we acquired gene expression data from eight commonly-used in vitro macrophage models to perform a meta-analysis. Specifically, we obtained gene expression data from unstimulated macrophages (M0) and macrophages stimulated with lipopolysaccharides (LPS) for 2-4 h (M-LPSearly), LPS for 24 h (M-LPSlate), LPS and interferon-γ (M-LPS+IFNγ), IFNγ (M-IFNγ), interleukin-4 (M-IL4), interleukin-10 (M-IL10), and dexamethasone (M-dex). Our meta-analysis identified consistently differentially expressed genes that have been implicated in inflammatory and metabolic processes. In addition, we built macIDR, a robust classifier capable of distinguishing macrophage activation states with high accuracy (>0.95). We classified in vivo macrophages with macIDR to define their tissue- and disease-specific characteristics. We demonstrate that alveolar macrophages display high resemblance to IL10 activation, but show a drop in IFNγ signature in chronic obstructive pulmonary disease patients. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but acquired LPS-activation features in diabetic-obese patients. Rheumatoid arthritis synovial macrophages exhibit characteristics of IL10- or IFNγ-stimulation. Altogether, we defined consensus transcriptional profiles for the eight in vitro macrophage activation states, built a classification model, and demonstrated the utility of the latter for in vivo macrophages.

KEYWORDS:

adipose tissue macrophages (ATMs); alveolar macrophages (AMs); elastic net classification; macrophage identifier (macIDR); macrophages; meta-analysis; synovial macrophages (SMs)

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