Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling

Abstract

	•Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.
	•Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling.
	•ISO promoted the assembly of CBM complex and then activated NF-κB signaling in macrophages through OTUD1-mediated deubiquitinating modification.
	•OTUD1 deletion in myeloid cells protected hearts from ISO-induced injuries in mice.

Keywords

CARD9 / heart failure / inflammation / isoproterenol / macrophage / OTUD1

References

[1] Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387-407.

[2] Chang SC, Ren S, Rau CD, et al. Isoproterenol-induced heart failure mouse model using osmotic pump implantation. Methods Mol Biol. 2018;1816:207-220.

[3] Hu G, Wu J, Gu H, et al. Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon β-adrenergic insult. Sci China Life Sci. 2023;66:1067-1078.

[4] Vendrov AE, Xiao H, Lozhkin A, et al. Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy. Redox Biol. 2023;67:102937.

[5] Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104-107.

[6] Toyoda S, Haruyama A, Inami S, et al. Effects of carvedilol vs bisoprolol on inflammation and oxidative stress in patients with chronic heart failure. J Cardiol. 2020;75:140-147.

[7] Murphy SP, Kakkar R, McCarthy CP, et al. Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:1324-1340.

[8] Cook C, Cole G, Asaria P, et al. The annual global economic burden of heart failure. Int J Cardiol. 2014;171:368-376.

[9] Hruz P, Eckmann L. Caspase recruitment domain-containing sensors and adaptors in intestinal innate immunity. Curr Opin Gastroenterol. 2008;24:108-114.

[10] Liu Y, Shao YH, Zhang JM, et al. Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression. Signal Transduct Target Ther. 2023;8:394.

[11] Li L, Wang X, Chen W, et al. Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction. Basic Res Cardiol. 2015;110:56.

[12] Zhao CH, Ma X, Guo HY, et al. RIP2 deficiency attenuates cardiac hypertrophy, inflammation and fibrosis in pressure overload induced mice. Biochem Biophys Res Commun. 2017;493:1151-1158.

[13] Lin HB, Naito K, Oh Y, et al. Innate immune Nod1/RIP2 signaling is essential for cardiac hypertrophy but requires mitochondrial antiviral signaling protein for signal transductions and energy balance. Circulation. 2020;142:2240-2258.

[14] Li L, Chen W, Zhu Y, et al. Caspase recruitment domain 6 protects against cardiac hypertrophy in response to pressure overload. Hypertension. 2014;64:94-102.

[15] Peterson MR, Getiye Y, Bosch L, et al. A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy. Hypertens Res. 2020;43:1375-1384.

[16] Zong J, Salim M, Zhou H, et al. NOD2 deletion promotes cardiac hypertrophy and fibrosis induced by pressure overload. Lab Invest. 2013;93:1128-1136.

[17] Schaefer BC. The CBM complex: a growing multiplicity of cellular functions, regulatory mechanisms and connections to human disease. Cell Immunol. 2020;356:104189.

[18] Qian J, Liang S, Wang Q, et al. Toll-like receptor-2 in cardiomyocytes and macrophages mediates isoproterenol-induced cardiac inflammation and remodeling. Faseb j. 2023;37:e22740.

[19] Qian JF, Liang SQ, Wang QY, et al. Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure. Acta Pharmacol Sin. 2023.

[20] Chen X, Qian J, Liang S, et al. Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes. Acta Pharm Sin B. 2024;14:1693-1710.

[21] Liu X, Jiang B, Hao H, et al. CARD9-mediated signaling and cardiovascular diseases. JACC Basic Transl Sci. 2022;7:406-409.

[22] Frieler RA, Mortensen RM. Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation. 2015;131:1019-1030.

[23] Colonna M. All roads lead to CARD9. Nat Immunol. 2007;8:554-555.

[24] Chen X, Zhang H, Wang X, et al. OTUD1 regulates antifungal innate immunity through deubiquitination of CARD9. J Immunol. 2021;206:1832-1843.

[25] Xu W, Rush JS, Graham DB, et al. USP15 deubiquitinates CARD9 to downregulate C-type lectin receptor-mediated signaling. Immunohorizons. 2020;4:670-678.

[26] Cao Z, Conway KL, Heath RJ, et al. Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. Immunity. 2015;43:715-726.

[27] Huang Z, Shen S, Wang M, et al. Mouse endothelial OTUD1 promotes angiotensin II-induced vascular remodeling by deubiquitinating SMAD3. EMBO Rep. 2023;24:e56135.

[28] Zhang Y, Vandestienne M, Lavillegrand JR, et al. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy. Nat Commun. 2023;14:4622.

[29] Li Y, Liang P, Jiang B, et al. CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly. Basic Res Cardiol. 2020;115:29.

[30] Ren J, Yang M, Qi G, et al. Proinflammatory protein CARD9 is essential for infiltration of monocytic fibroblast precursors and cardiac fibrosis caused by angiotensin II infusion. Am J Hypertens. 2011;24:701-707.

[31] Wang S, Gu J, Xu Z, et al. Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway. J Cell Mol Med. 2017;21:1182-1192.

[32] Wang M, Han X, Yu T, et al. OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. Theranostics. 2023;13:2263-2280.

[33] Cao L, Qin X, Peterson MR, et al. CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity. J Mol Cell Cardiol. 2016;92:185-195.

[34] Jaén RI, Val-Blasco A, Prieto P, et al. Innate immune receptors, key actors in cardiovascular diseases. JACC Basic Transl Sci. 2020;5:735-749.

[35] Liu X, Jiang B, Hao H, et al. CARD9 signaling, inflammation, and diseases. Front Immunol. 2022;13:880879.

[36] Staal J, Driege Y, Haegman M, et al. Defining the combinatorial space of PKC::CARD-CC signal transduction nodes. Febs j. 2021;288:1630-1647.

[37] Zhang Z, Fan Y, Xie F, et al. Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7. Nat Commun. 2017;8:2116.

[38] Oikawa D, Gi M, Kosako H, et al. OTUD1 deubiquitinase regulates NF-κB-and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways. Cell Death Dis. 2022;13:694.

[39] Wu B, Qiang L, Zhang Y, et al. The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling. Cell Mol Immunol. 2022;19:276-289.

[40] Lu H, Xie Y, Zhou Z, et al. Identification of novel targets for treatment of dilated cardiomyopathy based on the ferroptosis and immune heterogeneity. J Inflamm Res. 2023;16:2461-2476.

[41] Gross O, Gewies A, Finger K, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442:651-656.

[42] Campuzano A, Zhang H, Ostroff GR, et al. CARD9-associated dectin-1 and dectin-2 are required for protective immunity of a multivalent vaccine against Coccidioides posadasii infection. J Immunol. 2020;204:3296-3306.

[43] Ye S, Huang H, Han X, et al. Dectin-1 acts as a non-classical receptor of Ang II to induce cardiac remodeling. Circ Res. 2023;132:707-722.

[44] Chiffoleau E, C-Type. Lectin-like receptors as emerging orchestrators of sterile inflammation represent potential therapeutic targets. Front Immunol. 2018;9:227.

[45] Hara H, Ishihara C, Takeuchi A, et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol. 2007;8:619-629.

[46] Rhoads JP, Lukens JR, Wilhelm AJ, et al. Oxidized low-density lipoprotein immune complex priming of the Nlrp3 inflammasome involves TLR and FcγR cooperation and is dependent on CARD9. J Immunol. 2017;198:2105-2114.

[47] Yanan S, Bohan L, Shuaifeng S, et al. Inhibition of Mogroside IIIE on isoproterenol-induced myocardial fibrosis through the TLR4/MyD88/NF-κB signaling pathway. Iran J Basic Med Sci. 2023;26:114-120.

[48] Li Y, Liang P, Jiang B, et al. CARD9 inhibits mitochondria-dependent apoptosis of cardiomyocytes under oxidative stress via interacting with Apaf-1. Free Radic Biol Med. 2019;141:172-181.

[49] Zhou L, Miao K, Yin B, et al. Cardioprotective role of myeloid-derived suppressor cells in heart failure. Circulation. 2018;138:181-197.

[50] Gao MH, Lai NC, Giamouridis D, et al. Cardiac-directed expression of adenylyl cyclase catalytic domain reverses cardiac dysfunction caused by sustained beta-adrenergic receptor stimulation. JACC Basic Transl Sci. 2016;1:617-629.

[51] Peter AK, Walker CJ, Ceccato T, et al. Cardiac fibroblasts mediate a sexually dimorphic fibrotic response to β-Adrenergic stimulation. J Am Heart Assoc. 2021;10:e018876.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.