Exosome-mediated Cooperative Mechanisms of Macrophage/Fibroblast Activation in Systemic Sclerosis

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ABSTRACT Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology that is characterized by vasculopathy, fibrosis, and inflammation. There is no cure for SSc and there are very few FDA-approved disease- modifying treatments. While the contribution of fibroblasts to disease development is widely appreciated, recent studies suggest macrophages (MØs) also play a role in the pathogenesis of SSc. In recently published work, we developed an immunophenotypic profile for SSc MØs, and demonstrated that co-culture of MØs with SSc dermal fibroblasts resulted in mutual activation of these cell types. However, the factors responsible for SSc MØ activation are unknown. In this regard, our new preliminary studies implicate SSc dermal fibroblast-derived exosomes as mediators of MØ activation in SSc. We show that uptake of SSc dermal fibroblast-derived exosomes induces profibrotic MØ activation. In addition, SSc fibroblast-activated MØs stimulate SSc fibroblast production of inflammatory cytokines and extracellular matrix (ECM) components. Therefore, we hypothesize that exosome-stimulated MØs and SSc fibroblasts engage in reciprocal activation. The goal of this study is to determine the mechanisms through which secreted fibroblast-derived exosomes and MØs promote fibrotic and inflammatory activation in SSc. We will define the molecular mechanisms, pathways, and key molecules that mediate cross-talk between fibroblast exosomes and MØs in SSc, and will test the therapeutic efficacy of targeting these regulators using a recently developed 3D human SSc skin model. Results of this work will provide the rational basis for the development of novel and effective treatments for SSc. The aims that will be tested in this application are: 1. Define fibroblast exosomal cargo and identify the components that regulate MØ activation in SSc. Genomic and molecular biology approaches will be used to identify the exosome mediators that induce SSc MØ activation and to identify the signaling pathways that underlie this activation. 2. Determine how exosomal-mediated changes in MØ activation promote inflammation and fibrosis in SSc. Co-culture studies demonstrate that SSc MØs induce activation of SSc fibroblasts, implicating a role for MØ-derived factors in the induction and maintenance of fibrosis. This aim will determine how SSc MØ activation impacts fibroblast activation.