Caveolin-1 Deficiency May Predispose African Americans to Systemic Sclerosis–Related Interstitial Lung Disease

The prevalence of lung involvement in patients with systemic sclerosis (SSc; scleroderma) is >70 % (1), and lung disease is the primary cause of morbidity and mortality among these patients (2,3). Several studies (4–11) have revealed highly significant data demonstrating that SSc is more severe in African American individuals than in Caucasian individuals in terms of increased prevalence, earlier age at disease onset, increased risk of lung involvement, increased probability of having the more severe diffuse form of SSc, and increased mortality. In particular, African American patients with SSc also have significantly decreased lung function, including reductions in forced vital capacity and diffusing capacity for carbon monoxide. Such differences are not explained by socioeconomic status, access to health care, or autoantibody status (12). Although the focus on African American patients with SSc has been considerable, very few studies have addressed the underlying differences between healthy African American and Caucasian individuals that might result in a predisposition in the African American population toward SSc and ILD. Racial differences in the expression and function of various profibrotic and antifibrotic cytokines have been reported (12). Bogatkevich and colleagues observed that bronchoalveolar lavage (BAL) fluid from healthy African American individuals contains much higher levels of hepatocyte growth factor (HGF) and several other cytokines (insulin-like growth factor binding protein, osteoprotegerin, stem cell factor, thrombopoietin, and vascular endothelial growth factor) compared with BAL fluid from healthy Caucasians, and that lung fibroblasts from healthy African Americans are much less responsive to added HGF than are fibroblasts from healthy Caucasians (13). In another study, serum levels of the profibrotic cytokine transforming growth factor β (TGFβ) were twice as high in healthy African Americans as in healthy Caucasians (14). Caveolin-1, a protein associated with plasma membrane invaginations known as caveolae and with other cellular membranes, is a promising therapeutic target in patients with ILD, including patients with SSc-related ILD. Caveolin-1 binds to and thereby inhibits the function of kinases in several major signaling families including protein kinase C, MAPK, Src, and protein G (15–18) and regulates cell signaling and cell functions induced by the major profibrotic cytokine TGFβ (19–21). There are multiple points of intersection between TGFβ and caveolin-1 signaling. For example, TGFβ inhibits caveolin-1 expression in a variety of cell types including fibroblasts (lung and skin) and monocytes (22–24), suggesting that the TGFβ-rich milieu in the blood and tissue of patients with SSc may lead to reduced caveolin-1 expression in fibroblasts and monocytes and thereby to an altered behavior of these cells that promotes fibrosis. Caveolin-1 also modulates TGFβ signaling in dermal fibroblasts by inhibiting Smad3 phosphorylation and its translocation to the nucleus (24) and via its effects on the endocytosis of TGFβ ligand–receptor complexes. TGFβ receptors sort to both caveolin-1–rich lipid rafts and early endosomes (25,26). The internalization of TGFβ receptors is dependent on the function of caveolin-1 in lipid rafts and clathrin in early endosomes. Early endosomal internalization increases TGFβ signaling, while caveolin-1–dependent internalization leads to receptor degradation, thereby inhibiting TGFβ signaling (27). We and other investigators have demonstrated that caveolin-1 is deficient in the lung tissue of patients with SSc and those with idiopathic pulmonary fibrosis and in cells isolated from the lung tissue and blood of these patients, including fibroblasts, monocytes, and neutrophils (19,28,29). Similarly, caveolin-1 is deficient in mice in which ILD has been induced with bleomycin or irradiation (28,30). Caveolin-1–null mice spontaneously exhibit thickened, hypercellular alveolar walls and increased extracellular matrix deposition (31,32). The effects of caveolin-1 deficiency in cells and in animals can be reversed by using either the adenovirus encoding full-length caveolin-1 or the caveolin-1 scaffolding domain (CSD) peptide (19,28). When this 20–amino acid domain of caveolin-1 is synthesized in fusion with the antennapedia internalization sequence, it can enter cells and inhibit kinases much like full-length caveolin-1 (33,34). Thus, the central role that caveolin-1 plays in regulating inflammatory cell infiltration and fibrosis in the model of bleomycin-induced ILD has been demonstrated using the CSD peptide to reverse the deficiency of caveolin-1 in several cell types and thereby inhibit disease progression (28,29). In the course of studies of the role of caveolin-1 in the regulation of cell function and signaling in SSc, we made the unexpected and striking observation that many of the alterations in function and signaling observed in monocytes from patients with SSc were also observed in monocytes from healthy African Americans. Herein we have characterized several similarities and differences in monocyte function and signaling in monocytes from patients with SSc and healthy African American individuals. These similarities may contribute to the predisposition of African Americans to SSc and ILD.