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

Susan K. Mathai, Mridu Gulati, Xueyan Peng, Thomas R. Russell, Albert C. Shaw, Ami N. Rubinowitz, Lynne A. Murray, Jonathan M. Siner, Danielle E. Antin-Ozerkis, Ruth R. Montgomery, Ronald As Reilkoff, Richard J. Bucala, Erica L. Herzog

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

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 Luminexbased 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 ≤35 years, subjects ≥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.

Original languageEnglish (US)
Pages (from-to)812-823
Number of pages12
JournalLaboratory Investigation
Volume90
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part by awards from the NIH (P30AR053495-01A1, K08 HL079066, UL1 RR024139, and N01 A150031) an Edward Mallinckrodt, Jr Scholar Award, funds from the Yale Department of Medicine, and Promedior, Inc. (all to ELH).

Keywords

  • Alternative activation
  • Fibrocytes
  • Macrophages
  • Pulmonary fibrosis
  • Scleroderma

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