Transcriptional and Functional Diversity of Human Macrophage Repolarization

Publication date: Available online 14 November 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Sina A. Gharib, Ryan S. McMahan, William E. Eddy, Matthew E. Long, William C. Parks, Moira L. Aitken, Anne M. Manicone

Abstract

Background

Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma.

Objective

To examine the transcriptional and functional significance of macrophage repolarization from an "M1" towards an "M2" phenotype, and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation.

Methods

Monocyte-derived macrophages were collected from healthy and CF subjects and polarized to an M2 state using IL-4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS re-challenge and clear apoptotic neutrophils, and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthma.

Results

We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated pro-inflammatory pathways and abrogated LPS-tolerance allowing for rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS-tolerance, dampening pro-inflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2-state transcriptional patterns in alveolar macrophages.

Conclusion

Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different "M2" stimuli, and provide a framework to phenotype macrophages in disease states.

Graphical abstract

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