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

Scleroderma (systemic sclerosis, SSc) is a complex autoimmune connective tissue disease involving inflammation and fibrosis of the skin, lungs and other internal organs. The main cause of morbidity and mortality in SSc is interstitial lung disease (ILD). Until recently, lung fibrosis was generally believed to result from the proliferation and activation of resident connective tissue fibroblasts [1]. However, recent studies have also indicated that fibroblasts can be derived from hematopoietic cells and by epithelial- or endothelial-mesenchymal transformation. In fact, the notion that matrix-producing cells could be derived from peripheral blood mononuclear cells (PBMCs) peripheral blood cells is not new. It was suggested by Metchnikov and others 100 years ago [2-5].PBMCs play important roles in inflammation, fibrosis and wound healing because of their immune functions and because they are the progenitors of collagen-producing cells. The CD14+ monocyte fraction contains precursors not only for macrophages but also for fibrocytes. Circulating connective tissue cell progenitors (fibrocytes) were described previously [6] as a subpopulation of PBMCs that express collagen together with hematopoietic cell surface markers (for example C11b, CD34 and/or CD45), but that do not express CD14. In addition, a population of CD45+/CD14+/collagen I-positive (ColI+) cells described as "collagen-producing monocytes" was recently observed at much higher levels in the peripheral blood of SSc patients than in control subjects [7].Both monocytes and fibrocytes express on their surface the C-X-C chemokine receptor type 4 (CXCR4). CXCR4 mediates the migration of these cells in response to stromal cell-derived factor 1 (SDF-1, or CXCL12), which is expressed at high levels in injured human and mouse lung tissues [8]. In addition, fibrocytes contribute to tissue remodeling by producing high levels of cytokines, fibrogenic growth factors, extracellular matrix proteins and matrix metalloproteina