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

By Jia Xue, Susanne V. Schmidt, Jil Sander, Astrid Draffehn, Wolfgang Krebs, Inga Quester, Dominic De Nardo, Trupti D. Gohel, Martina Emde, Lisa M. Schmidleithner and 11 more. Immunity, 2014

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Summary Macrophage 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.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/28535d644612f0877a615c9b0d0b270e4f01310a

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Citations in the corpus

Macrophage Polarization. (2017, background): “DIFFERENCES BETWEEN HUMAN AND MOUSE MACROPHAGE POLARIZATION Differences between gene expression in human and rodent polarized macrophages have been discussed at length, along with similarities and differences between the species in terms of immunity in general (30, 99).”
Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span (2017, background): “This “macrophage polarization” model is based on limited evidence and is conceptually incomplete (Xue et al., 2014; Nahrendorf and Swirski, 2016).”
Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, background): “In general, based on Th1/Th2 polarization, M1 macrophages are pro-inflammatory and tumoricidal (classically activated), while M2 are anti-inflammatory and tumor supportive (alternatively activated) (Martinez et al., 2008; Gautier et al., 2012; Xue et al., 2014; You et al., 2015).”
Liver inflammation and fibrosis. (2017, background): “However, extensive transcriptome analysis for recruited macrophages in response to various stimuli revealed a spectrum of macrophage activation between the M1 and M2 poles (51).”
Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells (2020, methodology): “To further explore the activation state of T-MG and T-MDMs, we subjected their respective upregulated genes to ORA of macrophage stimulus-specific programs (Xue et al., 2014).”
Diversity, Mechanisms and Significance of Macrophage Plasticity (2019, background): “A systematic trasncriptional profiling effort of human macrophages exposed to== a wide range of signals (33) has further extended the spectrum of activation states well beyond the original M1/M2 dichotomy.”
Wound healing: cellular mechanisms and pathological outcomes (2020, background): “However, this dichotomous classification has become outdated, with both human [34] and murine [35] macrophages now known to showdiverse transcriptional andphenotypic responses to different stimuli (reviewed in [36]).”
The role of macrophages in the resolution of inflammation. (2019, background): “, who found that the M1/M2 paradigm failed to describe the transcriptome of human monocytederived and alveolar macrophages stimulated with LPS/IFN-γ or IL-4/IL-13 in the presence of factors known to be present in different tissue or disease microenvironments (42).”
Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets (2019, background): “Although macrophages were traditionally classified into M1 and M2 polarization states, more recent studies describe a spectrum of activation states (Xue et al., 2014) and an association of both states with tumor progression (Franklin et al.”
Tissue-Resident Macrophage Ontogeny and Homeostasis. (2016, background): “Given that macrophages can derive from embryonic progenitors or from BM monocytes and that they exhibit immense heterogeneity both in vitro (Xue et al., 2014) and in vivo (Gautier et al., 2012; Lavin et al., 2014), understanding how influences from their origin and environment are integrated to…”