Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide

Abstract

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.

Fibrocytes in Scleroderma Lung Fibrosis

“…These cells displayed enriched expression of CD34 and in some cases also expressed CD14, indicating both their multipotent potential as well as their monocytic origin. Since this work was first published these results have been confirmed by at least one other group (Tourkina et al, 2011) indicating the reproducibility of the fibrocyte assay in this patient population.…”

“…The ideal biomarker would be present in easily accessible clinical specimens, would be a potential contributor to disease development, and would be easily studied in murine models of disease. For this reason, peripheral blood fibrocytes have emerged as an exciting new area of study in the field of Scleroderma Mathai et al, 2010;Peng et al, 2011 ;Tourkina et al,2011;Reilkoff et al, 2011).…”

Fibrocytes in pulmonary fibrosis: a brief synopsis

“…There is evidence that these cells are involved in the pathogenesis of lung fibrosis [34], liver fibrosis [35], scleroderma [36,37] and asthma [38,39]. Fibrocytes have been identified in areas of injury adjacent to newly formed scar tissue, which has raised the question of whether or not these cells are good targets to improve repair and prevent fibrotic remodelling.…”

Lung Bone Marrow–derived Hematopoietic Progenitor Cells Enhance Pulmonary Fibrosis

“…conjunction with previous evidence for the importance of BM-derived cells (BMDCs) in fibrosis (13)(14)(15)(16), the expansion of the lung CFC population with its concomitant reduction in BM in response to lung injury suggests mobilization of BMderived HSCs may play a significant role in the subsequent fibrosis, although the identity or identities of the cells recruited to the lung and their roles in fibrosis remain uncertain. Hence, the objective of this study was to characterize the phenotype and role of BMDCs in pulmonary fibrosis using the rodent bleomycin (BLM) model.…”