Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation

Jia Xue,Jil Sander,Hariharasudan Ganesan,Marc Beyer,Lisa Schmidleithner,Inga Quester,Thomas Ulas,Wolfgang Krebs,Heidi Theis,Michael Kraut,Martina Emde,Eicke Latz,Larisa I Labzin ,Trupti D Gohel ,Astrid M Draffehn ,Andrea Niño‐Castro ,Tom C Freeman ,Dominic De Nardo ,Susanne V Schmidt ,Michael R Mallmann ,Joachim L Schultze

doi:10.1016/j.immuni.2014.01.006

Abstract

SummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Highlights

During the last two decades, a conceptual framework for the description of macrophage activation has been developed
With coregulation analysis (CRA) to assess overall sample-to-sample relationships, macrophages were clearly distinguishable from other cell types including dendritic cells (DCs) (Figures S1B–S1E), which was confirmed on protein level by flow cytometry (Figures S1F and S1G)
To better understand the complexity of transcriptional regulation after macrophage activation, we analyzed the transcriptional programs of macrophages activated with 28 different stimuli including pattern recognition receptor ligands, cytokines, and metabolic cues (Figure 1A)

Summary

Introduction

During the last two decades, a conceptual framework for the description of macrophage activation has been developed. Transcriptomics has considerably contributed to a better understanding of immune cell function and regulation Large consortia such as the ImmGen consortium (Best et al, 2013; Bezman et al, 2012; Cohen et al, 2013; Gautier et al, 2012; Miller et al, 2012) or the Human Immunology Project Consortium (Poland et al, 2013) compiled extensive data sets and defined a core transcriptional program for murine tissue macrophages and dendritic cells (DCs) under steady-state conditions (Gautier et al, 2012; Miller et al, 2012). Comparative studies have identified substantial differences in immune-cell gene expression between mice and humans (Schroder et al, 2012; Shay et al, 2013). It remains to be fully elucidated, how immune cell activation— in human macrophages—is transcriptionally controlled and to which degree these pathways are conserved across species

Results

Discussion

Conclusion