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. Epub 2021 Aug 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Differentiation / physiology
  • Chemokine CCL1 / metabolism*
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • Phosphoproteins / metabolism*
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Receptors, Autocrine Motility Factor / metabolism*
  • Signal Transduction / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokine CCL1
  • Membrane Proteins
  • Phosphoproteins
  • SPRY1 protein, human
  • Spry1 protein, mouse
  • Receptors, Autocrine Motility Factor