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

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

  • Immunity. 2021 Sep 14;54(9):2042-2056.e8. doi: 10.1016/j.immuni.2021.06.008.
Shan-Shan Liu 1,  Chang Liu 2,  Xiao-Xi Lv 2,  Bing Cui 2,  Jun Yan 3,  Yun-Xuan Li 2,  Ke Li 4,  Fang Hua 2,  Xiao-Wei Zhang 2,  Jiao-Jiao Yu 2,  Jin-Mei Yu 2,  Feng Wang 2,  Shuang Shang 2,  Ping-Ping Li 2,  Zhi-Guang Zhou 5,  Yang Xiao 6,  Zhuo-Wei Hu 7
Affiliations

Affiliations

  • 1 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3 Beijing Institute of Brain Disorders, Capital Medical University, Beijing 100050, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 5 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
  • 6 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China. Electronic address: xiaoyang29@csu.edu.cn.
  • 7 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: huzhuowei@csu.edu.cn.
PMID: 34407391 DOI: 10.1016/j.immuni.2021.06.008
Abstract

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.

Keywords

CCL1; E3 ligase; chemokine receptor; lung injury; myofibroblast activation; protein-protein interaction; pulmonary fibrosis; ubiquitination.

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