Systemic sclerosis (SSc) is a progressive fibrotic disease for which there is no effective treatment. Presently, the major cause of morbidity and mortality for patients with SSc is respiratory failure due to pulmonary fibrosis. Despite how commonly interstitial lung disease (ILD) occurs in SSc, it remains poorly understood and represents a major unmet medical need. The Wnt/?-catenin (?-cat) signaling pathway is known to be crucial for cell fate decisions throughout development and adult tissue repair after injury. Work from our group and others have shown that the Wnt/?-cat pathway is aberrantly activated in systemic sclerosis and the associated ILD. Subsequent studies from our laboratory provided the first evidence that global genetic loss of the Wnt co-receptor Lrp5, resulting in reduced ?-cat signaling, was protective against bleomycin-induced pulmonary fibrosis and that, in the peripheral blood mononuclear cells from two independent cohorts of Idiopathic Pulmonary Fibrosis (IPF) subjects, Wnt signaling as one of the top 2 over- represented pathways associated with worsened prognosis. We have generated extensive preliminary data demonstrating that sustained ?-cat signaling in lung macrophages promotes the persistence of lung fibrosis after both bleomycin- and asbestos-induced injuries in mice, suggesting that macrophages are a key cell type through which ?-cat signaling drives fibrosis. Our preliminary data also reveal that the alveolar macrophage population is increased in SSc-ILD lungs, where lung transcriptomes from SSc-ILD and IPF subjects share common genes. Thus, based on these findings, we reason that the signals that drive macrophage recruitment, differentiation and perdurance after tissue injury are conserved across fibrotic diseases through a common Wnt/?-cat regulatory axis. We hypothesize that Wnt/?-cat signaling is required for the differentiation of monocytes into recruited alveolar macrophages and that injured lung alveolar epithelium provides a contextual Wnt signal that maintains a pro-fibrotic milieu for these recruited macrophages, thus aggravating lung repair and promoting the persistence of fibrosis. We propose 1) to determine the role Wnt/?-cat signaling to the differentiation of monocytes-macrophages in the persistence of fibrosis in SSc-ILD, 2) to determine the contribution of Wnt signaling from the injured alveolar epithelium in maintaining the pro-fibrotic macrophage phenotype in SSc-ILD, and 3) to determine the monocyte- macrophage subpopulations from subjects with SSc-ILD that express enrichment for Wnt pathway genes. We will use human blood and lung samples from subjects with SSc-ILD and complementary in vivo approaches using competitive and shielded chimeric mice, macrophage-specific transgenic mice targeting ?-cat and Wnt ligands, and chemical ablation to dissect the relative contributions of Wnt/?-cat signaling in macrophages and epithelial cells necessary for repair after lung injury and in SSc-ILD where immune pathways are implicated.
The studies from this proposal will be the first to establish the link between the Wnt/?-catenin pathway and monocyte-macrophage differentiation in the resolution of pulmonary fibrosis after injury. This proposal deepen our understanding of Wnt/?-catenin interactions in alveolar macrophage-epithelial cell biology and demonstrate that, in both human and mouse, the Wnt/?- catenin pathway is critical in regulating lung monocyte-macrophage differentiation. These findings will further our current understanding regarding how host immune responses contribute to the persistent fibrotic reaction and represents a potential new area for prognosis and therapeutic intervention for SSc-ILD.
|Chiarella, Sergio E; Rabin, Erik E; Ostilla, Lorena A et al. (2018) ?T-catenin: A developmentally dispensable, disease-linked member of the ?-catenin family. Tissue Barriers 6:e1463896|