Macrophage-Specific NLRC5 Protects From Cardiac Remodeling Through Interaction With HSPA8

Overview

Journal JACC Basic Transl Sci

Date 2023 Jun 16

PMID 37325412

Authors

Qing Yu

Peinan Ju

Wenxin Kou

Ming Zhai

Yanxi Zeng

Nuerbiyemu Maimaitiaili

Yefei Shi

Xu Xu

Yifan Zhao

Weixia Jian

Mark W Feinberg

Yawei Xu

Jianhui Zhuang

Wenhui Peng

Affiliations

Soon will be listed here.

Abstract

Macrophages regulate inflammation and the process of tissue repair. Therefore, a better understanding of macrophages in the pathogenesis of heart failure is needed. In patients with hypertrophic cardiomyopathy, NLRC5 was significantly increased in circulating monocytes and cardiac macrophages. Myeloid-specific deletion of NLRC5 aggravated pressure overload-induced pathological cardiac remodeling and inflammation. Mechanistically, NLRC5 interacted with HSPA8 and suppressed NF-κB pathway in macrophages. The absence of NLRC5 in macrophages promoted the secretion of cytokines such as interleukin-6 (IL-6), which affected cardiomyocyte hypertrophy and cardiac fibroblast activation. Tocilizumab, an anti-IL-6 receptor antagonist, may be a novel therapeutic strategy for cardiac remodeling and chronic heart failure.

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References

Laroumanie F, Douin-Echinard V, Pozzo J, Lairez O, Tortosa F, Vinel C . CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation. 2014; 129(21):2111-24. DOI: 10.1161/CIRCULATIONAHA.113.007101. View

Takahashi T, Shishido T, Kinoshita D, Watanabe K, Toshima T, Sugai T . Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response. JACC Basic Transl Sci. 2019; 4(2):234-247. PMC: 6488753. DOI: 10.1016/j.jacbts.2018.11.011. View

Tong Y, Cui J, Li Q, Zou J, Wang H, Wang R . Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res. 2012; 22(5):822-35. PMC: 3343662. DOI: 10.1038/cr.2012.53. View

Gutte P, Jurt S, Grutter M, Zerbe O . Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain. Biochemistry. 2014; 53(19):3106-17. DOI: 10.1021/bi500177x. View

Huo S, Shi W, Ma H, Yan D, Luo P, Guo J . Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene. Oxid Med Cell Longev. 2021; 2021:6699054. PMC: 8007383. DOI: 10.1155/2021/6699054. View

Fajgenbaum D, June C . Cytokine Storm. N Engl J Med. 2020; 383(23):2255-2273. PMC: 7727315. DOI: 10.1056/NEJMra2026131. View

Patel B, Bansal S, Ismahil M, Hamid T, Rokosh G, Mack M . CCR2 Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload. JACC Basic Transl Sci. 2018; 3(2):230-244. PMC: 6059350. DOI: 10.1016/j.jacbts.2017.12.006. View

Davis B, Roberts R, Huang M, Willingham S, Conti B, Brickey W . Cutting edge: NLRC5-dependent activation of the inflammasome. J Immunol. 2010; 186(3):1333-7. PMC: 3669680. DOI: 10.4049/jimmunol.1003111. View

Mouton A, Li X, Hall M, Hall J . Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation. Circ Res. 2020; 126(6):789-806. PMC: 7255054. DOI: 10.1161/CIRCRESAHA.119.312321. View

10.

Wang B, Wu Y, Ge Z, Zhang X, Yan Y, Xie Y . NLRC5 deficiency ameliorates cardiac fibrosis in diabetic cardiomyopathy by regulating EndMT through Smad2/3 signaling pathway. Biochem Biophys Res Commun. 2020; 528(3):545-553. DOI: 10.1016/j.bbrc.2020.05.151. View

11.

Ridker P, Everett B, Thuren T, MacFadyen J, Chang W, Ballantyne C . Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017; 377(12):1119-1131. DOI: 10.1056/NEJMoa1707914. View

12.

Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E . Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016; 37(30):2406-13. DOI: 10.1093/eurheartj/ehw171. View

13.

Ridker P, Devalaraja M, Baeres F, Engelmann M, Hovingh G, Ivkovic M . IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021; 397(10289):2060-2069. DOI: 10.1016/S0140-6736(21)00520-1. View

14.

Sun K, Li Y, Jin J . A double-edged sword of immuno-microenvironment in cardiac homeostasis and injury repair. Signal Transduct Target Ther. 2021; 6(1):79. PMC: 7897720. DOI: 10.1038/s41392-020-00455-6. View

15.

Cui J, Zhu L, Xia X, Wang H, Legras X, Hong J . NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010; 141(3):483-96. PMC: 3150216. DOI: 10.1016/j.cell.2010.03.040. View

16.

Cai W, Zhang X, Yan H, Ma Y, Wang X, Yan J . Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice. Cardiovasc Res. 2010; 88(1):140-9. DOI: 10.1093/cvr/cvq182. View

17.

Shirakawa K, Endo J, Kataoka M, Katsumata Y, Yoshida N, Yamamoto T . IL (Interleukin)-10-STAT3-Galectin-3 Axis Is Essential for Osteopontin-Producing Reparative Macrophage Polarization After Myocardial Infarction. Circulation. 2018; 138(18):2021-2035. DOI: 10.1161/CIRCULATIONAHA.118.035047. View

18.

Martini E, Kunderfranco P, Peano C, Carullo P, Cremonesi M, Schorn T . Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation. Circulation. 2019; 140(25):2089-2107. DOI: 10.1161/CIRCULATIONAHA.119.041694. View

19.

Liu L, Wang Y, Cao Z, Wang M, Liu X, Gao T . Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction. J Cell Mol Med. 2015; 19(12):2728-40. PMC: 4687701. DOI: 10.1111/jcmm.12659. View

20.

Jaen R, Val-Blasco A, Prieto P, Gil-Fernandez M, Smani T, Lopez-Sendon J . Innate Immune Receptors, Key Actors in Cardiovascular Diseases. JACC Basic Transl Sci. 2020; 5(7):735-749. PMC: 7393405. DOI: 10.1016/j.jacbts.2020.03.015. View