Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype

Lab Invest. 2010 Jun;90(6):812-23. doi: 10.1038/labinvest.2010.73. Epub 2010 Apr 19.

Abstract

Profibrotic cells derived from circulating CD14+ monocytes include fibrocytes and alternatively activated macrophages. These cells are associated with interstitial lung disease (ILD) and are implicated in the pathogenesis of systemic sclerosis (SSc); however, the simultaneous presence of profibrotic cells and their associated mediators in the circulation of these patients has not been defined. We hypothesized that monocytes from patients with SSc-related ILD (SSc-ILD) would show profibrotic characteristics when compared with normal controls. We recruited patients with SSc-ILD (n=12) and normal controls (n=27) and quantified circulating collagen-producing cells by flow cytometry for CD45 and pro-collagen I. The in vitro activation potential of CD14+ monocytes in response to lipopolysaccharide was assessed using flow cytometry for CD163, and by ELISA for CCL18 and IL-10 secretion. Profibrotic mediators in plasma were quantified using Luminex-based assays. The concentration of circulating collagen-producing cells was increased in the SSc-ILD patients when compared with controls. These cells were composed of both CD34+ fibrocytes and a population of CD34+CD14+ cells. Cultured CD14+ monocytes from SSc-ILD patients revealed a profibrotic phenotype characterized by expression of CD163 and by enhanced secretion of CCL18 and IL-10 in response to proinflammatory activation. Plasma levels of IL-10, MCP-1, IL-1RA, and TNF levels were significantly elevated in the plasma of the SSc-ILD cohort. Subgroup analysis of the normal controls revealed that unlike the subjects < or =35 years, subjects > or =60 years old showed higher levels of circulating CD34+CD14+ cells, collagen-producing CD14+ monocytes, CD163+ monocytes, IL-4, IL-10, IL-13, MCP-1, and CCL18. These data indicate that the blood of patients with SSc-ILD and of healthy aged controls is enriched for fibrocytes, profibrotic monocytes, and fibrosis-associated mediators. Investigations defining the factors responsible for this peripheral blood profile may provide new insight into SSc-ILD as well as the pathophysiology of aging.

Publication types

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

MeSH terms

  • Adult
  • Cell Differentiation
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Leukocyte Common Antigens / blood
  • Lipopolysaccharide Receptors / blood
  • Lung Diseases, Interstitial / complications*
  • Lung Diseases, Interstitial / immunology
  • Lung Diseases, Interstitial / pathology
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / pathology
  • Monocytes / immunology
  • Monocytes / pathology
  • Monocytes / physiology*
  • Pulmonary Fibrosis / pathology*
  • Scleroderma, Systemic / blood*
  • Scleroderma, Systemic / complications*
  • Scleroderma, Systemic / immunology

Substances

  • Lipopolysaccharide Receptors
  • Leukocyte Common Antigens