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 2

Fibroblast Itgb8 regulates innate and adaptive immune responses to IT-Ad-IL-1β.

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Fibroblast Itgb8 regulates innate and adaptive immune responses to IT-Ad...
(A and B) IL-β–dependent increases in lymphocyte and neutrophil numbers are inhibited in Itgb8fko mice. BAL total cell counts (A) and differential (B) 7 days after IT-Ad-IL-1β in the presence (No Tam) or absence (Tam) of Itgb8 on fibroblasts. (C) Multicolor cell surface staining for lung CD4+ and CD8+ T cells, B cells, NK cells, PMNs, and macrophages (Macs) 14 days after IT-Ad-IL-1β treatment without or with fibroblast-specific deletion of Itgb8 (n = 3). Shown are gated cell numbers. (D) Multicolor intracellular staining of CD4+ cells for IL-17 and/or IFN-γ. Three populations are identified: Th-17 cells (IL-17+IFN-γ–), IFN-γ+ Th-17 cells (IL-17+IFN-γ+), and Th1 (IL-17–IFN-γ+). Shown are cell numbers. (E) ELISpot for IL-17. Shown are number of spots/106 plated cells. (F and G) Multicolor cell surface staining for lung mDCs 14 days after IT-Ad-IL-1β treatment without or with fibroblast-specific deletion of Itgb8 (n = 6) (F) or with control IgG or systemic anti–TGF-β (n = 6) (G). Gating strategy for lung DCs is shown in Supplemental Figure 4, based on published methodology (54, 88). Shown is the increase in numbers of each subset relative to control Ad-LacZ plus corn oil or Ad-LacZ plus tamoxifen. *P < 0.05, **P < 0.01, ***P < 0.001.