Systemic sclerosis (SSc) or scleroderma is a devastating disease characterized by cutaneous and visceral fibrosis affecting the skin and internal organs. Interstitial lung disease associated with systemic sclerosis (SSc- ILD) is a leading cause of death in this population and is associated with hyper-responsiveness to transforming growth factor beta 1 (TGF-?1) and accumulation of fibrocytes in the blood and lung parenchyma of affected individuals. Despite ongoing efforts, the mechanisms promoting fibrocyte accumulation and disease progression in SSc-ILD remain unclear. Semaphorin 7a (Sema 7a) is part of a family of highly conserved membrane bound and secreted proteins that appear to be important in regulating neuronal and immune system functions. We have shown that hematopoietic expression of Sema 7a is sufficient to induce fibrosis and fibrocyte accumulation in a murine model of pulmonary fibrosis caused by transgenic overexpression of TGF-?1. Sema 7A signals through two known receptors, the stimulatory receptor ?-1 integrin subunit and the inhibitory receptor Plexin C1. Recent work by our lab in animal models and primary human cells has shown that ?-1 integrin promotes Sema 7a induced pulmonary fibrosis and fibrocyte accumulation. The role of Plexin C1 is less well understood and thus is the focus of this research proposal. Plexin C1 is a large transmembrane glycoprotein important in immunomodulation and tumor invasion. We have previously shown that Plexin C1 mRNA is elevated in the circulation of patients with SSc-ILD, and that Plexin C1 suppresses human fibrocyte development in primary human cell cultures. Our preliminary data shows that Plexin C1 expression is increased in both the bleomycin exposed murine lung and the TGF-?1 transgenic lung specific murine model. However, its effect on fibrocyte accumulation and fibrosis in vivo and its relationship to fibrocyte development in ILD remain undefined. In this study, we propose to test the hypotheses that 1) Plexin C1 is increased on fibrocyte precursors in the blood of SSc-ILD patients where it functions to impede fibrocyte differentiation and 2) Plexin C1 deletion promotes fibrocyte accumulation and lung fibrosis in two murine models of experimentally induced lung fibrosis. Fluorescent antibody cell sorting, primary human cell culture and animal modeling will be used to test our hypotheses. If successful, these studies could lead to novel insights into the immunopathogenesis of pulmonary fibrosis that might one day allow Plexin C1-based therapeutics.
The aim of the proposed study is to elucidate the contribution of Plexin C1, a protein present on cells in the immune system, to the pathology of a specific type of lung fibrosis that develops in patients with scleroderma. Using two distinct mouse models and blood from patients with scleroderma, we propose to define the mechanisms by which Plexin C1 contributes to lung fibrosis, with the ultimate goal of developing Plexin C1- based therapies for those suffering from this deadly disease.