Cpg-ODN, a TLR9 Agonist, Aggravates Myocardial Ischemia/Reperfusion Injury by Activation of TLR9-P38 MAPK Signaling

Abstract

Background/Aims: Toll-like receptors (TLRs) have been implicated in myocardial ischemia/ reperfusion (I/R) injury. We examined the effect of CpG-oligodeoxynucleotide (ODN) on myocardial I/R injury. Methods: Male Sprague-Dawley rats were treated with either CpG-ODN or control ODN 1 h prior to myocardial ischemia (30 min) followed by reperfusion. Rats treated with phosphate-buffered saline (PBS) served as I/R controls (n = 8/group). Infarct size was determined by 2,3,5-triphenyltetrazolium chloride and Evans blue straining. Cardiac function was examined by echocardiography before and up to 14 days after myocardial I/R. Results: CpG-ODN administration significantly increased infarct size and reduced cardiac function and survival rate after myocardial I/R, compared to the PBS-treated I/R group. Control-ODN did not alter I/R-induced myocardial infarct size, cardiac dysfunction, and survival rate. Additionally, CpG-ODN promoted I/R-induced myocardial apoptosis and cleaved caspase-3 levels in the myocardium. CpG-ODN increased TLR9 activation and p38 phosphorylation in the myocardium. In vitro data also suggested that CpG-ODN treatment induced TLR9 activation and p38 phosphorylation. Importantly, p38 mitogen-activated protein kinase (MAPK) inhibition abolished CpG-ODN-induced cardiac injury. Conclusion: CpG-ODN, the TLR9 ligand, accelerates myocardial I/R injury. The mechanisms involve activation of the TLR9-p38 MAPK signaling pathway.

Hederagenin Attenuates Cerebral Ischaemia/Reperfusion Injury by Regulating MLK3 Signalling

“…In addition, HE decreased the production of intracellular reactive oxygen species in ovariectomy-induced bone loss through the inhibition of p38 and Erk signalling. Although there is no clearly defined mechanism for HE on ischaemia/reperfusion injury, other studies have implicated the involvement of the MAPK pathway ( Li et al, 2017 ; Xie et al, 2018 ). Intriguingly, HE induced the activation of JNK, but not ERK or p38.…”

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

“…The ability of CpG‐rich mitochondrial DNA to trigger TLR9 activation has led to the appropriate use of CpG‐ODN for the study of multiple disease states where mitochondrial stress and injury are believed to play a pathogenic role 51–56 . These include atherosclerosis, 10–14 ischaemia‐reperfusion, 11,15–19,94 infection/sepsis, 20–37 and various autoimmune diseases 38–50 . Due to the direct link between mitochondrial stress and intracellular calcium dyshomeostasis, 84–86 the effect of intracellular calcium on CpG‐ODN‐mediated innate immune signalling is relevant to the study of these disease states associated with sterile inflammation.…”

“…Exogenous CpG‐oligodeoxynucleotides (ODN) stimulate TLR9 mediate innate immune signalling, and have been used to study the pathogenesis of sterile inflammation. CpG‐ODN has been used to study atherosclerosis, 10–14 ischaemia‐reperfusion, 11,15–19 infection/sepsis, 20–37 and various autoimmune diseases 38–50 . Importantly, mitochondrial stress and injury has also been implicated in the pathogenesis of atherosclerosis, 51 ischaemia‐reperfusion, 52,53 infection, 54,55 and various autoimmune diseases 56 .…”

Evaluation of long-term antibody response and cross-serotype reaction in ducks immunised with recombinant Riemerella anatipestifer outer membrane protein A and CpG ODN

“…The increase in IL-6 represented activation of type 2 helper T (Th2) cells, which are important for humoral immunity. The balance between Th1 and Th2 cells is important in the immune responses, suggesting that both humoral and cell-mediated immunities were induced after vaccination (23).…”