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

• Published in: The Journal of clinical investigation 2011-07, Vol.121 (7), p.2863-2875
• Main Authors: Kitamura, Hideya, Cambier, Stephanie, Somanath, Sangeeta, Barker, Tyren, Minagawa, Shunsuke, Markovics, Jennifer, Goodsell, Amanda, Publicover, Jean, Reichardt, Louis, Jablons, David, Wolters, Paul, Hill, Arthur, Marks, James D, Lou, Jianlong, Pittet, Jean-Francois, Gauldie, Jack, Baron, Jody Lynn, Nishimura, Stephen L
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement - immunology; Chemokines - immunology; Cytokines - immunology; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - physiology; Fibrosis - metabolism; Humans; Integrins - genetics; Integrins - immunology; Interleukin-1beta - immunology; Interleukin-1beta - pharmacology; Lung - cytology; Lung - immunology; Lung - pathology; Mice; Pneumonia - immunology; Pulmonary Disease, Chronic Obstructive - immunology; Pulmonary Disease, Chronic Obstructive - pathology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI45589

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-β-activating integrin αvβ8 and neutralization of αvβ8 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 αvβ8-mediated activation of TGF-β by fibroblasts. Our data therefore indicate that fibroblasts have a crucial role in regulating both fibrotic and immune responses in the lung.