Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis

Cell Rep Med. 2020 Nov 17;1(8):100140. doi: 10.1016/j.xcrm.2020.100140.

Abstract

Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.

Trial registration: ClinicalTrials.gov NCT01532869 NCT02453256.

Keywords: IL-6; ILD; SPP1; SSc; biomarker; fibrosis; immune complex; macrophages; osteopontin; systemic sclerosis.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / metabolism
  • Biomarkers / metabolism
  • Cell Line
  • Chemokines, CC / metabolism
  • Disease Progression
  • Fibrosis / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Lung / metabolism
  • Lung Diseases, Interstitial / metabolism
  • Macrophages / metabolism
  • Monocytes / metabolism
  • Myeloid Cells / metabolism*
  • Osteopontin / metabolism*
  • Scleroderma, Systemic / metabolism*

Substances

  • Autoantibodies
  • Biomarkers
  • Chemokines, CC
  • Interleukin-6
  • Osteopontin

Associated data

  • ClinicalTrials.gov/NCT01532869
  • ClinicalTrials.gov/NCT02453256