Dataset Information

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

ABSTRACT: Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

SUBMITTER: Meli VS

PROVIDER: S-EPMC7717914 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

Meli Vijaykumar S VS Atcha Hamza H Veerasubramanian Praveen Krishna PK Nagalla Raji R RR Luu Thuy U TU Chen Esther Y EY Guerrero-Juarez Christian F CF Yamaga Kosuke K Pandori William W Hsieh Jessica Y JY Downing Timothy L TL Fruman David A DA Lodoen Melissa B MB Plikus Maksim V MV Wang Wenqi W Liu Wendy F WF

Science advances 20201204 49

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate ...[more]

PMID: 33277245

Similar Datasets

Project description:BackgroundInflammatory response after myocardial infarction (MI) is essential for cardiac healing, whereas excessive and prolonged inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanistic insight of these tightly controlled inflammatory processes has a significant impact on post-MI recovery and therapy. Here, we uncover the critical role of small GTPase RhoE in post-MI recovery and its clinical implication.MethodsThree genetic mouse lines are used: global RhoE knockout, cardiomyocyte-specific RhoE heterozygous, and cardiomyocyte-specific RhoE overexpression mice. A set of molecular signaling experiments, including bimolecular fluorescence complementation, immunoprecipitation, electrophoretic mobility shift assay, and mRNA microarray analysis, were conducted. Permanent ligation of the left anterior descending artery was performed, followed by the assessments of cardiac function, inflammation, and survival in the first week after MI. Finally, we examined the correlation of the expression levels of RhoE in MI patient heart and patient prognosis.ResultsRhoE deficiency turns on a group of proinflammatory gene expressions in mouse heart. Mice with cardiomyocyte-specific haploinsufficiency exhibit excessive inflammatory response with deleterious cardiac function after MI. A profound increase in nuclear factor-κB activity is detected in the mutant heart and the isolated cardiomyocytes. We further find that the expression of RhoE is upregulated in response to MI. Mechanistically, RhoE interacts with p65 and p50 individually in cytosol and blocks their nuclear translocation. RhoE also occupies the dimerization domain of p65 and subsequently disrupts the heterodimerization between p65 and p50. Cardiac RhoE overexpression inhibits nuclear factor-κB activity, restrains post-MI inflammation, and improves cardiac function and survival. Consistently, we find that the expression level of RhoE is elevated in the heart of patients with MI and that the patients with a higher expression level of RhoE exhibit a better prognosis in cardiac function recovery.ConclusionsThe study uncovers RhoE as a new fine-tuning factor modulating MI-induced inflammation and promoting injured heart recovery. RhoE may serve as a new potential biomarker for the assessment of MI patient prognosis. Manipulation of RhoE could be as a potential therapeutic approach for MI and other inflammatory diseases.

Dataset Information

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

Publications

YAP-mediated mechanotransduction tunes the macrophage inflammatory response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets