Abstract
AbstractPulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung disease characterized by the scarring of lung due to excessive production of extracellular matrix (ECM). Recent studies have revealed the impact of macrophages in inflammation-induced fibrosis and distinct subsets of macrophages differentially contributes to the development of PF. However, the regulatory mechanisms and proinflammatory/profibrotc behaviour of heterogeneous population of lung macrophages during fibrogenesis remain incompletely understood. Here, we demonstrate the macrophage-specific role of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the development of bleomycin-induced inflammation and PF in mice. Both YAP/TAZ are activated in lung macrophages of fibrotic patients and of mice after bleomycin-induced injury. Myeloid-specific genetic deletion ofYap/Tazresulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs), leading to an impaired inflammatory response, reduced PF and improved regeneration of alveolar epithelial cells in bleomycin-injured lung. However, overexpression ofYapin macrophages augmented the Mo-AMs recruitment in lung leading to increased proinflammatory response, exacerbated fibrotic response and decreased regeneration of alveolar epithelial cells in bleomycin-injured lung. We demonstrate that YAP/TAZ regulate PF through the activation of macrophage recruitment driver C-C motif chemokine ligand 2 (CCL2) and blocking of CCL2 with neutralizing antibody prevented YAP-induced inflammatory and fibrotic response. We also demonstrate that YAP/TAZ regulate macrophage polarization as well as macrophage-fibroblasts crosstalk by regulating expression of Methyl-CpG–binding domain 2 (MBD2) during bleomycin-induced PF. Taken together, we show that YAP/TAZ are potent regulators of macrophage polarization, infiltration and macrophage–mediated proinflammatory/profibrotic response during PF.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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