Pulmonary fibrosis is the result of dysregulated repair after tissue injury. Idiopathic pulmonary fibrosis (IPF) remains a devastating, progressive disease with no known cure and currently no treatment that effectively alters the disease course. While the inciting etiology of IPF is still not clear, increasing evidence suggests that host immune responses contribute to the persistent fibrotic reaction and represents a potential new area for therapeutic intervention. The Wnt/β-catenin pathway has been well described as a determiner of cell fate; recent studies showed that canonical Wnt/β-catenin signaling plays a pivotal role in myeloid cell activation in the gastrointestinal tract and skin. Studies from our lab demonstrate that global loss of the Wnt co-receptor Lrp5 is protective against bleomycin-induced pulmonary fibrosis and gene expression analysis of Lrp5-null lungs indicates that the pathways most perturbed are related to immune response and extracellular matrix turnover. Consistent with these microarray data, flow cytometry analysis reveals that Wnt/β-catenin signaling is highly activated in lung myeloid cells and that β-catenin/Lrp5 signaling alters macrophage differentiation/activation. Collectively, our data strongly suggest that sustained Wnt signaling is a driver of lung fibrosis and that key Wnt-activated cell types include immune cells. We hypothesize that β-catenin signaling promotes the differentiation of monocytes into recruited alveolar macrophages, which ultimately impacts the innate immune response and aggravates tissue repair. We predict that inhibition of β-cat signaling in monocyte-derived macrophages promotes the resolution of pulmonary fibrosis (Aim 1). We propose that canonical Wnt/β-catenin is required for differentiation of monocyte-derived alveolar macrophages after lung injury (Aim 2). Thus we anticipate that Wnt/β-catenin dysregulation in a subpopulation of PBMCs can be used to predict disease outcome in patients with IPF (Aim 3). Recruitment of macrophages to the lungs after injury is critical not only for host defense but also tissue repair. This proposal focuses on a novel and important area of investigation linking a key developmental pathway to the innate immune response in lung repair. The findings from this proposal will be the first to establish the role of the Wnt/β-catenin pathway in macrophage differentiation/activation in the innate immune response for resolution of lung injury.
|Effective start/end date||9/15/16 → 8/31/18|
- National Heart, Lung, and Blood Institute (1R56HL127245-01A1)
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