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Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin ?v?8-mediated activation of TGF-?.

ABSTRACT: The airway is a primary portal of entry for noxious environmental stimuli that can trigger airway remodeling, which contributes significantly to airway obstruction in chronic obstructive pulmonary disease (COPD) and chronic asthma. Important pathologic components of airway remodeling include fibrosis and abnormal innate and adaptive immune responses. The positioning of fibroblasts in interstitial spaces suggests that they could participate in both fibrosis and chemokine regulation of the trafficking of immune cells such as dendritic cells, which are crucial antigen-presenting cells. However, physiological evidence for this dual role for fibroblasts is lacking. Here, in two physiologically relevant models - conditional deletion in mouse fibroblasts of the TGF-?-activating integrin ?v?8 and neutralization of ?v?8 in human COPD fibroblasts - we have elucidated a mechanism whereby lung fibroblast chemokine secretion directs dendritic cell trafficking, in a manner that is critically dependent on ?v?8-mediated activation of TGF-? by fibroblasts. Our data therefore indicate that fibroblasts have a crucial role in regulating both fibrotic and immune responses in the lung.

SUBMITTER: Kitamura H

PROVIDER: S-EPMC3223836 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β.

Kitamura Hideya H Cambier Stephanie S Somanath Sangeeta S Barker Tyren T Minagawa Shunsuke S Markovics Jennifer J Goodsell Amanda A Publicover Jean J Reichardt Louis L Jablons David D Wolters Paul P Hill Arthur A Marks James D JD Lou Jianlong J Pittet Jean-Francois JF Gauldie Jack J Baron Jody Lynn JL Nishimura Stephen L SL

The Journal of clinical investigation 20110606 7

The airway is a primary portal of entry for noxious environmental stimuli that can trigger airway remodeling, which contributes significantly to airway obstruction in chronic obstructive pulmonary disease (COPD) and chronic asthma. Important pathologic components of airway remodeling include fibrosis and abnormal innate and adaptive immune responses. The positioning of fibroblasts in interstitial spaces suggests that they could participate in both fibrosis and chemokine regulation of the traffic ...[more]

PMID: 21646718

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Project description:Asthma is the most common chronic lung disease in children and young adults worldwide. Airway remodelling (including increased fibroblasts and myofibroblasts in airway walls due to chronic inflammation) differentiates asthmatic from non-asthmatic airways. The increase in airway fibroblasts and myofibroblasts occurs via epithelial to mesenchymal transition (EMT) where epithelial cells lose their tight junctions and are transdifferentiated to mesenchymal cells, with further increases in myofibroblasts occurring via fibroblast-myofibroblast transition (FMT). Transforming growth factor (TGF)-? is the central EMT- and FMT-inducing cytokine. In this study, we have used next generation sequencing to delineate the changes in the transcriptome induced by TGF-? treatment of WI-38 airway fibroblasts in both the short term and after differentiation into myofibroblasts, to gain an understanding of the contribution of TGF-? induced transdifferentiation to the asthmatic phenotype. The data obtained from RNAseq analysis was confirmed by quantitative PCR (qPCR) and protein expression investigated by western blotting. As expected, we found that genes coding for intermediates in the TGF-? signalling pathways (SMADs) were differentially expressed after TGF-? treatment, SMAD2 being upregulated and SMAD3 being downregulated as expected. Further, genes involved in cytoskeletal pathways (FN1, LAMA, ITGB1) were upregulated in myofibroblasts compared to fibroblasts. Importantly, genes that were previously shown to be changed in asthmatic lungs (ADAMTS1, DSP, TIMPs, MMPs) were similarly differentially expressed in myofibroblasts, strongly suggesting that TGF-? mediated differentiation of fibroblasts to myofibroblasts may underlie important changes in the asthmatic airway. We also identified new intermediates of signalling pathways (PKB, PTEN) that are changed in myofibroblasts compared to fibroblasts. We have found a significant number of genes that are altered after TGF-? induced transdifferentiation of WI-38 fibroblasts into myofibroblasts, many of which were expected or predicted. We also identified novel genes and pathways that were affected after TGF-? treatment, suggesting additional pathways are activated during the transition between fibroblasts and myofibroblasts and may contribute to the asthma phenotype.

Dataset Information

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin ?v?8-mediated activation of TGF-?.

Publications

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β.

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