Pro-Fibrotic Effects of CCL18 on Human Lung Fibroblasts Are Mediated via CCR6
Kerstin Höhne,
Annett Wagenknecht,
Corinna Maier,
Peggy Engelhard,
Torsten Goldmann,
Stephan J. Schließmann,
Till Plönes,
Martin Trepel,
Hermann Eibel,
Joachim Müller-Quernheim,
Gernot Zissel
Affiliations
Kerstin Höhne
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Annett Wagenknecht
Department of Medicine I, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Corinna Maier
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Peggy Engelhard
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Torsten Goldmann
Histology, Research Center Borstel, 23845 Borstel, Germany
Stephan J. Schließmann
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Till Plönes
Department of Thoracic Surgery, Center for Surgery, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Martin Trepel
Department of Medicine I, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Hermann Eibel
Center for Chronic Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Joachim Müller-Quernheim
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Gernot Zissel
Department of Pneumology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities. Methods: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines. Results: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression. Conclusion: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.
