Wnt/beta-catenin signaling impacts macrophage differentiation in persistence of pulmonary fibrosis

    Project: Research project

    Project Details

    Description

    Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease that is thought to result from dysregulated tissue repair. Core embryonic developmental pathways appear to be altered in IPF, including the Wnt/β-catenin pathway. Our lab was the first to demonstrate that global genetic loss of the Wnt co-receptor Lrp5 protects from lung fibrosis in a mouse model of IPF; we demonstrated that peripheral blood mononuclear cells from patients with IPF showed abnormal expression of the Wnt co-receptors, which correlated with disease prognosis. We found that loss of Lrp5/β-catenin signaling in mice altered differentiation of macrophages after lung injury, such that there were fewer recruited, monocyte-derived alveolar macrophages that contribute to persistence of fibrosis. Studies in which both wild-type and Lrp5-null bone marrow cells are transplanted into the same wild-type recipient mouse revealed decreased differentiation of Lrp5-null bone marrow cells into alveolar macrophages. These findings indicate that Wnt/β-catenin signaling is critical to monocyte-macrophage differentiation. Loss of β-catenin in macrophages demonstrated improved resolution of lung fibrosis after injury, supporting an important functional role of β-catenin mediated macrophage differentiation. As the Wnt/β-catenin pathway is known to determine cell fate, we hypothesize that Lrp5/β-catenin signaling promotes the differentiation of monocytes into recruited alveolar macrophages, which aggravates tissue repair. The findings from this proposal will provide insights into how a developmental pathway, Wnt/-cat, affects macrophage biology and will have broad implications for our understanding of tissue repair and homeostasis.
    StatusFinished
    Effective start/end date7/1/166/30/18

    Funding

    • Respiratory Health Association of Metropolitan Chicago (RHA2016-01-IPF)

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