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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Research Article Pulmonology

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 3

Fibroblast deletion of Itgb8 or systemic neutralization of TGF-β inhibits the IT-Ad-IL-1β–induced increase in DC subsets in the MLN due to decreased DC trafficking from the lung to the MLN.

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Fibroblast deletion of Itgb8 or systemic neutralization of TGF-β inhibit...
(A) Time course of IT-Ad-IL-1β–induced increases in DCs in the MLN and dependence on Itgb8 (n = 6, each time point). Col-Cre-ER(T);Itgb8fl/– mice were treated with IT-Ad-IL-1β with or without tamoxifen and the MLN harvested 7 or 14 days later. Gating strategy and representation of CD8α+, CD4+, 103+, 103– and inflammatory DCs are identical to those in Ballesteros-Tato et al., with the exception that CD4–CD8α– DCs are not shown (54). Shown is the increase in cell number relative to the controls. (B) MLN DC subpopulations of IT-Ad-IL-1β–treated mice (14 days) without and with systemic anti–TGF-β (n = 6). Shown is the increase in cell number minus the controls. (C) MLN gating strategy (MHC-II [Ia] versus CD11c), with percentage of cells shown within each gate. (D) The percentages of gated MHC-IIhiCD11chi DCs positive or negative for 103 are shown. Indicated in C are gates used for identification of CD4+ and CD8α+ conventional DCs and inflammatory DCs (iDC). (E and F) CFSE-labeled BMDCs (2 × 106/ mouse) were injected into the lateral tail vein 12 days after IT-Ad-IL-1β or Ad-C treatment and 36 hours prior to lung (E) and MLN (F) harvest of mice without or with fibroblast deletion of Itgb8 (n = 9). Numbers of MHC-IIhiCD11c+ CFSE-labeled cells are shown. *P < 0.05, **P < 0.01.