Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8–mediated activation of TGF-β
Hideya Kitamura, … , Jody Lynn Baron, Stephen L. Nishimura
Hideya Kitamura, … , Jody Lynn Baron, Stephen L. Nishimura
Published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2863-2875. https://doi.org/10.1172/JCI45589.
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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

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-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.

Authors

Hideya Kitamura, Stephanie Cambier, Sangeeta Somanath, Tyren Barker, Shunsuke Minagawa, Jennifer Markovics, Amanda Goodsell, Jean Publicover, Louis Reichardt, David Jablons, Paul Wolters, Arthur Hill, James D. Marks, Jianlong Lou, Jean-Francois Pittet, Jack Gauldie, Jody Lynn Baron, Stephen L. Nishimura

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Figure 4

Cytokine profiling and collagen expression analysis reveal that IT-Ad-IL-1β induces an αvβ8-dependent profibrogenic and proinflammatory phenotype.

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Cytokine profiling and collagen expression analysis reveal that IT-Ad-IL...
(A) qPCR of mouse lung homogenates 14 days after IT-Ad-IL-1β treatment without or with fibroblast deletion of Itgb8 (n = 6). Shown are copy number increases relative to control mice. (B) IL-1β treatment of mouse lung fibroblasts induces a sustained induction of collagen expression that is dependent on Itgb8 and TGF-β. Mouse lung fibroblasts were cultured from lungs of Itgb8fl/fl mice and treated with Ad-Cre or Ad-LacZ (Ad-C) (2.5 × 106 PFU) overnight prior to treatment with recombinant IL-1β (1 ng/ml) with isotype control mAb or anti–TGF-β (40 μg/ml). Cells were lysed 72 hours or 1 week later, and Sircol assay was performed to determine collagen concentration. CCL2 (C and E) and CCL20 (D and F) as measured by ELISA from Itgb8fl/fl mouse lung fibroblasts treated with Ad-Cre or anti–TGF-β (C and D) or from whole lung homogenates or BAL from Col-CreER(T);Itgb8fl/– mice 14 days after IT-Ad-IL-1β without or with tamoxifen (E and F). *P < 0.05, **P < 0.01, ***P < 0.001.