The TLR9 Ligand, CpG‐ODN, Induces Protection against Cerebral Ischemia/Reperfusion Injury via Activation of PI3K/Akt Signaling

Chen, Lu; Ha, Tuanzhu; Wang, Xiaohui; Liu, Li; Zhang, Xia; Kimbrough, Erinmarie Olson; Sha, Zhanxin; Guan, Meijian; Schweitzer, John B.; Kalbfleisch, John H.; Williams, David L.; Li, Chuanfu

doi:10.1161/jaha.113.000629

Cited by 60 publications

(56 citation statements)

References 48 publications

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“…Although immune activators have demonstrated success as prophylactic treatments for reduction of brain injury in experimental models of cerebral ischemia [13, 14, 24-28], their modulation of inflammation has dampened enthusiasm for clinical use. Systemic infection is often associated with poorer outcomes in stroke patients [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury

Bahjat

West

Kohama

et al. 2017

Transl. Stroke Res.

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Ischemia-reperfusion brain injury can be iatrogenically-induced secondary to life-saving procedures. Prophylactic treatment of these patients offers a promising prevention for life-long complications. We postulate that a CpG oligodeoxynucleotide (ODN) can provide robust antecedent protection against cerebral ischemic injury with minimal release of pro-inflammatory cytokines, making it an ideal candidate for further clinical development. Mouse and nonhuman primate (NHP) models of cerebral ischemic injury were used to test whether an A-type CpG ODN, which induces minimal systemic inflammatory cytokine responses, can provide prophylactic protection. Extent of injury in the mouse was measured by histological staining of live tissue. In the NHP, injury was assessed 2 and 7 days post-occlusion from T2-weighted magnetic resonance images and neurological and motor deficits were cataloged daily. Plasma cytokine levels were measured using species specific Luminex assays. Prophylactic administration of an A-type CpG ODN provided robust protection against cerebral ischemic injury in the mouse with minimal systemic inflammation. Rhesus macaques treated with D192935, a mixture of human optimized A-type CpG ODNs, had smaller infarcts and demonstrated significantly less neurological and motor deficits following ischemic injury. Our findings demonstrate the translational potential of D19293 5 as a prophylactic treatment for patients at risk of cerebral ischemic injury.

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Section: Discussionmentioning

confidence: 99%

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury

Bahjat

West

Kohama

et al. 2017

Transl. Stroke Res.

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“…Although TLR9 plays important roles in immune responses, its potential benefit for the treatment of ischemic diseases independent of inflammation has recently attracted attention. It has been reported that CpG‐ODN preconditioning induces protection against cerebral and myocardial ischemia/reperfusion injury by activating the PI3K/Akt pathway (Cao et al, ; Lu et al, ). Moreover, CpG‐ODN postconditioning also improves cardiac function after myocardium ischemic/reperfusion injury by activating the TLR9/PI3K pathway (Kim et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Male C57BL/6 mice at 8–10 weeks of age were randomized to receive an intraperitoneal (i.p.) injection of CpG‐ODNs (1 mg/kg body weight) 2 hr prior to left anterior descending artery (LAD) ligation surgery as previously described (Lu et al, ). For certain experiments confirming the efficiency of lentiviral infection in vivo, lentiviruses were injected into the myocardium 3 days prior to MI induction to first upregulate or downregulate TLR9 expression.…”

Section: Methodsmentioning

confidence: 99%

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Zhou

Jiang³

et al. 2017

Journal Cellular Physiology

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Unmethylated CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG-ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG-ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG-ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826-CpG and KSK-CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non-CpG controls. Histological analysis further confirmed the cardioprotection of CpG-ODN preconditioning. In vitro studies further demonstrated that CpG-ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9-mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG-ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non-CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG-ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG-ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG-ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG-ODN preconditioning may be useful in MI therapy.

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“…TLR9's role in I/R is controversial. Previous studies have found that TLR9 activates the downstream PI3K pathway, and numerous studies have found that this is a protective pathway in cardiac muscle [13,[26][27][28][29][30]. However, TLR9 can also activate other signaling pathways, such as those found to have a role in myocardial injury.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

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

Xie

Kong

et al. 2018

Cell Physiol Biochem

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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.

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The TLR9 Ligand, CpG‐ODN, Induces Protection against Cerebral Ischemia/Reperfusion Injury via Activation of PI3K/Akt Signaling

Cited by 60 publications

References 48 publications

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

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

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