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.
Highlights
Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure
Cytokine secretion analyses demonstrated a significant induction of IL-8, IL-1β, TNF-α, IL-6 and IL-10 release 48 hours post infection (Fig. 1) To corroborate our findings, we measured the same cytokine panel after infection of human blood-derived macrophages with L. pneumophila (Supplementary Fig. S1) and observed an induction pattern similar to THP-1 cells
The concentration of TNF-α needed for IL-8 induction were approximately 40-fold higher than the cytokine amounts released by THP-1 cells in response to L. pneumophila infection (Supplementary Figs S2b and 1c)
Summary
Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. 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. Monocytes as well as epithelial cells were demonstrated to be activated through T-cell-derived IL-17 subsequently enabling neutrophil-mediated host defense[16]
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