DOI: 10.1101/2023.05.24.542136

YAP/TAZ are Crucial Regulator of Macrophage-mediated Pulmonary Inflammation and Fibrosis after Bleomycin-induced Injury

M. K.Singh M. M. Mia S. A. B. Abdul Ghani D. M. Cibi H. Bogireddi W.-S. Wong

摘要

Pulmonary fibrosis (PF) is the most common form of end stage interstitial lung disease characterized by the scarring of lung. Recent studies 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 unclear. Here, we demonstrate the macrophage-specific role of YAP and TAZ in the development of bleomycin-induced inflammation and PF in mice. Myeloid-specific genetic deletion of Yap/Taz resulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs), leading to an impaired inflammatory response and reduced PF in bleomycin-injured lung. However, overexpression of Yap in macrophages augmented Mo-AMs recruitment in lung leading to increased proinflammatory response and exacerbated fibrotic response after bleomycin-injury. We demonstrate that YAP/TAZ regulate PF through the activation of macrophage recruitment driver CCL2. We also demonstrate that YAP/TAZ regulate macrophage polarization and macrophage-fibroblasts crosstalk through MBD2. Taken together, we show that YAP/TAZ are potent regulators of macrophage polarization, infiltration and macrophage-mediated proinflammatory/profibrotic response during PF.

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