Details

Autor(en) / Beteiligte

• Liu, Shan-shan
• Liu, Chang
• Lv, Xiao-xi
• Cui, Bing
• Yan, Jun
• Li, Yun-xuan
• Li, Ke
• Hua, Fang
• Zhang, Xiao-wei
• Yu, Jiao-jiao
• Yu, Jin-mei
• Wang, Feng
• Shang, Shuang
• Li, Ping-ping
• Zhou, Zhi-guang
• Xiao, Yang
• Hu, Zhuo-wei

Titel

The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis

Ist Teil von

• Immunity (Cambridge, Mass.), 2021-09, Vol.54 (9), p.2042-2056.e8

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases. [Display omitted] •CCL1 expression positively correlates with the development of lung fibrosis•CCL1 exerts its fibrogenic activity by signaling through AMFR on fibroblasts•CCL1-AMFR interaction relieves Spry1-repressed Ras-ERK-p70S6K activity•Suppression of the CCL1-AMFR-Ras-ERK-p70S6K axis reduces lung fibrosis Pulmonary fibrosis therapies require improved understanding of the underlying inflammatory mechanisms of disease. Liu et al. demonstrate that immune-derived CCL1 promotes lung fibrosis by two pathways: (1) recruiting CCR8-expressing fibroblasts to the lung and (2) activating lung fibroblasts into pathological myofibroblasts by binding AMFR on fibroblasts, which enhances Ras-ERK signaling and synthesis of profibrotic proteins.