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Abstract
Idiopathic pulmonary fibrosis (IPF) represents the most aggressive form of pulmonary fibrosis (PF) and is a highly debilitating disorder with a poorly understood etiology. The lung epithelium seems to play a critical role in the initiation and progression of the disease. A repeated injury of lung epithelial cells prompts type II alveolar cells to secrete pro-fibrotic cytokines, which induces differentiation of resident mesenchymal stem cells into myofibroblasts, thus promoting aberrant deposition of extracellular matrix (ECM) and formation of fibrotic lesions. Reactivation of developmental pathways such as the Wnt-β-catenin signaling cascade in lung epithelial cells plays a critical role in this process, but the underlying mechanisms are still enigmatic. Here, we demonstrate that the membrane-associated protein NUMB is required for pathological activation of β-catenin signaling in lung epithelial cells following bleomycin-induced injury. Importantly, depletion of Numb and Numblike reduces accumulation of fibrotic lesions, preserves lung functions, and increases survival rates after bleomycin treatment of mice. Mechanistically, we demonstrate that NUMB interacts with casein kinase 2 (CK2) and relies on CK2 to activate β-catenin signaling. We propose that pharmacological inhibition of NUMB signaling may represent an effective strategy for the development of novel therapeutic approaches against PF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder characterized by increased deposition of extracellular matrix (ECM), which results in pathological changes of lung architecture and deterioration of lung functions, leading to death (Todd et al, 2012; Raghu et al, 2018)
We found that inactivation of Numb and Numblike in the lung epithelium diminishes the formation of ATII cells, reduces β-catenin signaling, and attenuates lung fibrosis following bleomycin-induced lung injury
Since the activation of Wntβ-catenin signaling in lung epithelial cells plays a critical role in promoting lung fibrosis, we analyzed whether NUMB influences the expression and activation of β-catenin
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder characterized by increased deposition of extracellular matrix (ECM), which results in pathological changes of lung architecture and deterioration of lung functions, leading to death (Todd et al, 2012; Raghu et al, 2018). Activation of resident mesenchymal stem cells (MSCs) and subsequent differentiation into ECM-secreting myofibroblasts are assumed to be the principal causes for accumulation of fibrotic. It is currently assumed that critical events in the pathogenesis of IPF include repetitive injuries of ATII cells such as chronic endoplasmic reticulum stress (Korfei et al, 2018) and subsequent accumulation of cellular dysfunctions such as loss of stemness, increased apoptosis, and induction of senescence, among others (Tanjore et al, 2011; Hill et al, 2019; Parimon et al, 2020). Dysfunctional ATII cells promote the accumulation of fibrotic lesions by paracrine signals that act as pro-fibrotic factors by stimulating proliferation and differentiation of resident MSCs and lipofibroblasts into myofibroblasts (Tanjore et al, 2011; Selman and Pardo, 2012, 2014). The molecular mechanisms responsible for the aberrant activation and dysfunction of AECs still remain poorly understood, reactivation of molecular signaling pathways involved in lung development such as Wnt-β-catenin, Sonic Hedgehog, and Notch may play a decisive role in this process (Selman et al, 2008; Aoyagi-Ikeda et al, 2011; Baarsma and Konigshoff, 2017)
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