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Sci Rep. 2017 Sep 20;7(1):11988. doi: 10.1038/s41598-017-12154-4.

THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila - a systems biology study.

Author information

1
Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany.
2
Laboratory of Systems Tumor Immunology, Department of Dermatology, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
3
Institute for Lung Research/iLung, Research Group "RNA-Biology of Inflammation & Infection", Philipps University, Marburg, Germany.
4
Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité - University Medicine Berlin, Berlin, Germany.
5
Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany. bernd.schmeck@uni-marburg.de.
6
Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany. bernd.schmeck@uni-marburg.de.

Abstract

Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1β inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.

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