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.
View: Text | PDF
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

×

Figure 1

IT administration of adenovirus expressing human active IL-1β (IT-Ad-IL-1β) induces airway remodeling, which is dependent on αvβ8-mediated activation of TGF-β by fibroblasts.

Options: View larger image (or click on image) Download as PowerPoint
IT administration of adenovirus expressing human active IL-1β (IT-Ad-IL-...
(A–H) IT-Ad-IL-1β or Ad-control (Ad-C) was administered to adult mice to induce airway remodeling. (A–D) In Ad-IL-1β– (B) but not Ad-C–treated mice (A), 7 days after treatment, inflammation surrounds small airways (arrows, B), with increased collagen (arrowheads, D). Scale bar: 150 μm. (E) ELISA for IL-1β. (F) qPCR for Itgb8 (P = 0.01); (G) Serpine1 (P = 0.01); (H) Col1a2 (P = 0.04). (I) TGF-β bioassay of active and total TGF-β in BAL fluid from Itgb8fl/– mice (n = 6) 14 days after IT-Ad-IL-1β without or with IT-Ad-Cre. (J) Mice treated with IT-Ad-IL-1β with or without systemic administration of control antibody, anti-β6, or anti–TGF-β were evaluated at 14 days. (K–N) IT-Ad-IL-1β or Ad-C was administered to adult Itgb8fl/– mice expressing Cre-ER(T) under control of the fibroblast-specific Col1a2 promoter treated without or with tamoxifen (Tam). Tamoxifen causes specific deletion of Itgb8 in fibroblasts (Itgb8fko). (K and L) Inflammation (K, left) or fibrosis (L, left) is diminished in Itgb8fko mice (airway lumen, A). Arrows indicate inflammation in K; and arrowheads, collagen bundles, at low and high magnification (inset) in L in the presence of vehicle (K and L, left) or tamoxifen (K and L, right). Scale bar: 250 μm; 40 μm (inset). (M and N) Inflammation (M) or fibrosis (N) 7, 14, 21, or 42 days after IT-Ad-IL-1β without or with fibroblast-specific deletion of Itgb8. Shown are values minus the non–IT-Ad-IL-1β–treated controls. Raw data are shown in Supplemental Table 1. *P < 0.05, **P ≤ 0.01, ***P < 0.001.