https://doi.org/10.4081/ejh.2024.4019
Pretreatment with interleukin-15 attenuates inflammation and apoptosis by inhibiting NF-κB signaling in sepsis-induced myocardial dysfunction
Submitted: 13 March 2024
Accepted: 16 April 2024
Published: 29 April 2024
Accepted: 16 April 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.
Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018;392:75-87.
DOI: https://doi.org/10.1016/S0140-6736(18)30696-2
Mankowski RT, Yende S, Angus DC. Long-term impact of sepsis on cardiovascular health. Intens Care Med 2019;45:78-81.
DOI: https://doi.org/10.1007/s00134-018-5173-1
Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Resp Crit Care 2016;193:259-72.
DOI: https://doi.org/10.1164/rccm.201504-0781OC
Hollenberg SM, Singer M. Pathophysiology of sepsis-induced cardiomyopathy. Nat Rev Cardiol 2021;18:424-34.
DOI: https://doi.org/10.1038/s41569-020-00492-2
Vincent JL. Current sepsis therapeutics. Ebiomedicine 2022;86:104318.
DOI: https://doi.org/10.1016/j.ebiom.2022.104318
Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 1996;4:329-36.
DOI: https://doi.org/10.1016/S1074-7613(00)80246-0
Ward PA. The curiosity of IL-15. Nat Med 2007;13:903-4.
DOI: https://doi.org/10.1038/nm0807-903
Manohar M, Kandikattu HK, Verma AK, Mishra A. IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis. Am J Physiol-Gastr L 2018;315:G954-65.
DOI: https://doi.org/10.1152/ajpgi.00139.2018
Patidar M, Yadav N, Dalai SK. Interleukin 15: A key cytokine for immunotherapy. Cytokine Growth F R 2016;31:49-59.
DOI: https://doi.org/10.1016/j.cytogfr.2016.06.001
Hangasky JA, Chen W, Dubois SP, Daenthanasanmak A, Muller JR, Reid R, et al. A very long-acting IL-15: implications for the immunotherapy of cancer. J Immunother Cancer 2022;10-23.
DOI: https://doi.org/10.1136/jitc-2021-004104
Ameri K, Bayardorj D, Samurkashian R, Fredkin M, Fuh E, Nguyen V, et al. Administration of interleukin-15 peptide improves cardiac function in a mouse model of myocardial infarction. J Cardiovasc Pharm 2020;75:98-102.
DOI: https://doi.org/10.1097/FJC.0000000000000764
Bigalke B, Schwimmbeck PL, Haas CS, Lindemann S. Effect of interleukin-15 on the course of myocarditis in Coxsackievirus B3-infected BALB/c mice. Can J Cardiol 2009;25:e248-54.
DOI: https://doi.org/10.1016/S0828-282X(09)70511-2
Yeghiazarians Y, Honbo N, Imhof I, Woods B, Aguilera V, Ye J, et al. IL-15: a novel prosurvival signaling pathway in cardiomyocytes. J Cardiovasc Pharm 2014;63:406-11.
DOI: https://doi.org/10.1097/FJC.0000000000000061
Wuttge DM, Eriksson P, Sirsjo A, Hansson GK, Stemme S. Expression of interleukin-15 in mouse and human atherosclerotic lesions. Am J Pathol 2001;159:417-23.
DOI: https://doi.org/10.1016/S0002-9440(10)61712-9
Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol 2011;19:198-208.
DOI: https://doi.org/10.1016/j.tim.2011.01.001
Song Y, Zhang C, Zhang J, Jiao Z, Dong N, Wang G, et al. Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction. Theranostics 2019;9:2346-60.
DOI: https://doi.org/10.7150/thno.29945
Cai ZL, Shen B, Yuan Y, Liu C, Xie QW, Hu TT, et al. The effect of HMGA1 in LPS-induced Myocardial Inflammation. Int J Biol Sci 2020;16:1798-810.
DOI: https://doi.org/10.7150/ijbs.39947
Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007;35:1599-608.
DOI: https://doi.org/10.1097/01.CCM.0000266683.64081.02
Li Z, Zhu H, Liu C, Wang Y, Wang D, Liu H, et al. GSK-3beta inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity. J Cell Mol Med 2019;23:7796-809.
DOI: https://doi.org/10.1111/jcmm.14656
Li N, Zhou H, Wu H, Wu Q, Duan M, Deng W, et al. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol 2019;24:101215.
DOI: https://doi.org/10.1016/j.redox.2019.101215
Jia L, Wang Y, Wang Y, Ma Y, Shen J, Fu Z, et al. Heme oxygenase-1 in macrophages drives septic cardiac dysfunction via suppressing lysosomal degradation of inducible nitric oxide synthase. Circ Res 2018;122:1532-44.
DOI: https://doi.org/10.1161/CIRCRESAHA.118.312910
Ma H, Wang X, Ha T, Gao M, Liu L, Wang R, et al. MicroRNA-125b prevents cardiac dysfunction in polymicrobial sepsis by targeting TRAF6-mediated nuclear factor kappaB activation and p53-mediated apoptotic signaling. J Infect Dis 2016;214:1773-83.
DOI: https://doi.org/10.1093/infdis/jiw449
Luo Q, Ma H, Guo E, Yu L, Jia L, Zhang B, et al. MicroRNAs promote the progression of sepsis-induced cardiomyopathy and neurovascular dysfunction through upregulation of NF-kappaB signaling pathway-associated HDAC7/ACTN4. Front Neurol 2022;13:909828.
DOI: https://doi.org/10.3389/fneur.2022.909828
Xin Y, Tang L, Chen J, Chen D, Wen W, Han F. Inhibition of miR‑101‑3p protects against sepsis‑induced myocardial injury by inhibiting MAPK and NF‑kappaB pathway activation via the upregulation of DUSP1. Int J Mol Med 2021;47-58.
DOI: https://doi.org/10.3892/ijmm.2021.4853
Liang W, Li J, Bai C, Chen Y, Li Y, Huang G, et al. Interleukin-5 deletion promotes sepsis-induced M1 macrophage differentiation, deteriorates cardiac dysfunction, and exacerbates cardiac injury via the NF-kappaB p65 pathway in mice. Biofactors 2020;46:1006-17.
DOI: https://doi.org/10.1002/biof.1681
Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci 2012;33:35-41.
DOI: https://doi.org/10.1016/j.tips.2011.09.004
Hiromatsu T, Yajima T, Matsuguchi T, Nishimura H, Wajjwalku W, Arai T, et al. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-alpha-induced apoptosis. J Infect Dis 2003;187:1442-51.
DOI: https://doi.org/10.1086/374643
Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol 2010;184:1401-9.
DOI: https://doi.org/10.4049/jimmunol.0902307
Borowiec A, Kontny E, Smolis-Bak E, Kowalik I, Majos E, Zalucka L, et al. Prospective assessment of cytokine IL-15 activity in patients with refractory atrial fibrillation episodes. Cytokine 2015;74:164-70.
DOI: https://doi.org/10.1016/j.cyto.2015.04.002
Sharma AC. Sepsis-induced myocardial dysfunction. Shock 2007;28:265-9.
DOI: https://doi.org/10.1097/01.shk.0000235090.30550.fb
Liu YC, Yu MM, Shou ST, Chai YF. Sepsis-induced cardiomyopathy: mechanisms and treatments. Front Immunol 2017;8:1021.
DOI: https://doi.org/10.3389/fimmu.2017.01021
Wang X, Zingarelli B, O'Connor M, Zhang P, Adeyemo A, Kranias EG, et al. Overexpression of Hsp20 prevents endotoxin-induced myocardial dysfunction and apoptosis via inhibition of NF-kappaB activation. J Mol Cell Cardiol 2009;47:382-90.
DOI: https://doi.org/10.1016/j.yjmcc.2009.05.016
Yang X, Sun J, Sun F, Yao Y, Tian T, Zhou J, et al. TRIM31 promotes apoptosis via TAK1-mediated activation of NF-kappaB signaling in sepsis-induced myocardial dysfunction. Cell Cycle 2020;19:2685-700.
DOI: https://doi.org/10.1080/15384101.2020.1826235
Xu X, Rui S, Chen C, Zhang G, Li Z, Wang J, et al. Protective effects of astragalus polysaccharide nanoparticles on septic cardiac dysfunction through inhibition of TLR4/NF-kappaB signaling pathway. Int J Biol Macromol 2020;153:977-85.
DOI: https://doi.org/10.1016/j.ijbiomac.2019.10.227
Han X, Chen D, Liufu N, Ji F, Zeng Q, Yao W, et al. MG53 protects against sepsis-induced myocardial dysfunction by upregulating peroxisome proliferator-activated receptor-alpha. Oxid Med Cell Longev 2020;2020:7413693.
DOI: https://doi.org/10.1155/2020/7413693
Zeng N, Jian Z, Zhu W, Xu J, Fan Y, Xiao F. KLF13 overexpression protects sepsis-induced myocardial injury and LPS-induced inflammation and apoptosis. Int J Exp Pathol 2023;104:23-32.
DOI: https://doi.org/10.1111/iep.12459
Ethics Approval
the animal experiments were conducted according to protocols approved by the Animal Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of MedicineSupporting Agencies
Zhejiang Provincial Natural Science Foundation of China, National Natural Science Foundation of ChinaHow to Cite
He, C., Yu, Y., Wang, F., Li, W., Ni, H., & Xiang, M. (2024). Pretreatment with interleukin-15 attenuates inflammation and apoptosis by inhibiting NF-κB signaling in sepsis-induced myocardial dysfunction. European Journal of Histochemistry, 68(2). https://doi.org/10.4081/ejh.2024.4019
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