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Isolation of Macrophage Subsets and Stromal Cells from Human and Mouse Myocardial Specimens
Published on: December 17, 2019
Macrophage USP7 aggravates acute myocardial infarction by inhibiting STING degradation through the ESCRT pathway
Wenqian Qi1, Ruiqing Ren1, Liwen Yu1
1State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Insights
USP7 deubiquitinating enzyme regulates STING ubiquitination and degradation, suppressing cardiac inflammation in acute myocardial infarction (AMI). USP7 inhibition offers a potential therapeutic strategy for AMI by reducing macrophage inflammatory responses.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Macrophage-driven inflammation is central to acute myocardial infarction (AMI) progression.
- Elevated USP7 expression is observed in peripheral blood mononuclear cells (PBMCs) of coronary artery disease (CAD) patients.
Purpose of the Study:
- To investigate the role of USP7 in macrophage-mediated inflammation during AMI.
- To elucidate the molecular mechanism by which USP7 influences STING signaling and cardiac injury.
Main Methods:
- Macrophage-specific USP7 knockout mouse model of myocardial infarction (MI).
- Analysis of STING ubiquitination, degradation via the ESCRT-lysosomal pathway, and inflammatory signaling.
- Pharmacological inhibition and adenovirus-mediated knockdown of USP7.
Main Results:
- Macrophage-specific USP7 knockout suppressed cardiac inflammation post-AMI in mice.
- USP7 directly interacted with STING, suppressing its K63-linked ubiquitination at K289 and preventing degradation.
- USP7 ablation's cardioprotective effects were reversed by STING overexpression.
- USP7 inhibition or knockdown attenuated AMI-induced cardiac injury and inflammation.
Conclusions:
- USP7 is a novel deubiquitinating enzyme regulating STING ubiquitination and degradation through the ESCRT pathway.
- USP7 critically controls macrophage inflammatory responses in the context of AMI.
- Targeting USP7 presents a potential therapeutic avenue for mitigating cardiac inflammation in AMI.
Abstract:
Macrophage-driven inflammation plays a critical role in the progression of acute myocardial infarction (AMI). This study revealed that USP7 expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Furthermore, in a mouse model of myocardial infarction (MI), after AMI cardiac inflammation was suppressed by macrophage-specific USP7 knockout. Mechanistically, USP7 directly interacted with STING and suppressed its K63-linked ubiquitination at residue K289, thereby preventing STING degradation via the endosomal sorting complex required for transport (ESCRT)-lysosomal pathway and enhancing STING-mediated inflammatory signaling. The cardioprotective effects of USP7 ablation were abrogated by STING overexpression. Moreover, pharmacological inhibition of USP7 or adenovirus-mediated knockdown of USP7 similarly attenuated AMI-induced cardiac injury and inflammation in mice. These findings identify USP7 as a novel deubiquitinating enzyme that regulates STING ubiquitination and degradation via the ESCRT pathway, thus establishing USP7 as a critical regulator of macrophage inflammatory responses in AMI.
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