title: Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype.
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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Mathai
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Russell
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
authors.forename: Ami N
authors.initials: AN
authors.lastname: Rubinowitz
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Murray
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Siner
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Antin-Ozerkis
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Ronald A S
authors.initials: RA
authors.lastname: Reilkoff
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bucala
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D017493:Leukocyte Common Antigens / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000097:blood; D017563:Lung Diseases, Interstitial / Q000150:complications* / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000473:pathology*; D012595:Scleroderma, Systemic / Q000097:blood* / Q000150:complications* / Q000276:immunology
chemical_list: D018950:Lipopolysaccharide Receptors; D017493:Leukocyte Common Antigens
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