Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis

• Published in: Translational research : the journal of laboratory and clinical medicine 2024-06, Vol.268, p.1-12
• Main Authors: Cheng, Tzu-Yu, Chen, Yao-Chang, Li, Shao-Jung, Lin, Fong-Jhih, Lu, Yen-Yu, Lee, Ting-I, Lee, Ting-Wei, Higa, Satoshi, Kao, Yu-Hsun, Chen, Yi-Jen
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Atrial fibrillation (AF); Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Atrial Remodeling - drug effects; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calcium–calmodulin-dependent protein kinase II (CaMKII); Cell Line; Heart Atria - drug effects; Heart Atria - metabolism; Heart Atria - pathology; Heart Atria - physiopathology; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33 (IL-33); Interleukin-33 - metabolism; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Ryanodine receptor 2 (RyR2); Signal Transduction; Suppression of tumorigenicity 2 (ST2)
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2024.01.006

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium–calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.