Splenic monocytes mediate inflammatory response and exacerbate myocardial ischemia/reperfusion injury in a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion

• Published in: Basic research in cardiology 2023-10, Vol.118 (1), p.44-44, Article 44
• Main Authors: Xie, Dina, Guo, Hanliang, Li, Mingbiao, Jia, Liqun, Zhang, Hao, Liang, Degang, Wu, Naishi, Yang, Zequan, Tian, Yikui
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Cardiology; Caspase-1; CD11b antigen; Cell activation; Cell-Free Nucleic Acids; Coronary artery; Deoxyribonucleic acid; DNA; Heart surgery; Humans; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammatory response; Inhibitors; Injuries; Ischemia; Macrophages; Medicine; Medicine & Public Health; Mice; Mitochondrial DNA; Monocytes; Monocytes - metabolism; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial ischemia; Myocardial Reperfusion Injury - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Occlusion; Oligomerization; Original Contribution; Pyrin protein; Reperfusion; Reperfusion Injury; Spleen; Spleen - metabolism; Splenectomy; Splenocytes; TLR9 protein; Toll-Like Receptor 9; Toll-like receptors
• ISSN: 1435-1803; 0300-8428; 1435-1803
• DOI: 10.1007/s00395-023-01014-0

The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) recruits inflammasomes, initiating inflammatory responses and mediating tissue injury. We hypothesize that myocardial cell-free DNA (cfDNA) activates the splenic NLRP3 inflammasome during early reperfusion, increases systemic inflammatory response, and exacerbates myocardial infarct. Mice were subjected to 40 min of ischemia followed by 0, 1, 5, or 15 min, or 24 h of reperfusion. Splenic leukocyte adoptive transfer was performed by injecting isolated splenocytes to mice with splenectomy performed prior to left coronary artery occlusion. CY-09 (4 mg/kg) was administered 5 min before reperfusion. During post-ischemic reperfusion, splenic protein levels of NLRP3, cleaved caspase-1, and interleukin-1β (IL-1β) were significantly elevated and peaked (2.1 ± 0.2-, 3.4 ± 0.4-, and 3.2 ± 0.2-fold increase respectively, p