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 7

COPD fibroblasts have an enhanced profibrogenic phenotype and promote increased DC migration after IL-1β stimulation due to increased αvβ8-dependent TGF-β activation.

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COPD fibroblasts have an enhanced profibrogenic phenotype and promote in...
(A) ITGB8 determined by qPCR from normal and COPD fibroblasts treated with IL-1β (n = 5, P = 0.03). (B) Collagen in cell lysates from normal and COPD fibroblasts (n = 5) treated with or without IL-1β with isotype control, anti-β8, or anti–TGF-β. (C) TGF-β activation was measured by bioassay (arbitrary light units). (D) Selected human cytokine antibody array data (relative spot intensity). See Supplemental Figure 9 for complete array data. ELISA for CCL2 (E) and CCL20 (F). Results are expressed as fold increase compared with non–IL-1β–treated cells (n = 5). (G) Murine BMDC migration to fibroblast conditioned media (CM) or serum-free DMEM (Media). Mouse Itgb8fl/fl fibroblasts were treated with or without IL-1β in the presence of Ad-Cre, anti–TGF-β, or isotype control for 48 hours (n = 6). (H) Migration of wild-type, Ccr2–/–, or Ccr6–/– BMDCs (n = 3). (I) Migration of wild-type BMDCs to untreated or IL-1β–treated mouse lung fibroblast CM in the presence of anti-CCL2, anti-CCL20, or both antibodies combined (n = 3). (J) Migration of human cord blood–derived DCs to unstimulated (Control) or IL-1β–stimulated isotype control–, anti-β8–, or anti–TGF-β–treated pooled normal and COPD fibroblast CM (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001.