Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8–mediated activation of TGF-β
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
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
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 9

Model for fibroblast αvβ8–directed DC migration in airway remodeling.

Options: View larger image (or click on image) Download as PowerPoint
Model for fibroblast αvβ8–directed DC migration in airway remodeling. (i...
(i) Injury (i.e., tobacco smoke) or antigen (Ag) leads to inflammasome activation and caspase-1–mediated cleavage and release of active IL-1β. (ii) IL-1β is released by epithelial cells or macrophages. (iii) IL-1β increases αvβ8 expression by fibroblasts, which leads to increased conversion of latent to active TGF-β. (iv) Active TGF-β binds to fibroblast TGF-β receptors, leading to increased TGF-β–dependent chemokine (CCL2, CCL20) secretion and increased recruitment of DCs from the peripheral circulation. (v) Immature DCs encounter Ag within the epithelium or lamina propria and migrate toward fibroblasts via αvβ8-dependent chemotactic gradients. (vi) Mature DCs gain access to draining lymphatics. (vii) Mature DCs enter the draining MLN, where they prime adaptive immune responses. (viii) Differentiated memory/effector lymphocytes migrate to the airway to establish pathologic inflammation.