Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation

Abstract

The aim of the study was to investigate whether pre-conditioning with CpG-oligodeoxynucleotides (CpG-ODN) may change cardiac ischemia/reperfusion (I/R)-dependent inflammation and modulates infarct size and cardiac performance. WT and TLR9-deficient mice were pre-treated with 1668-, 1612- and H154-thioate or D-Gal as control. Priming with 1668-thioate significantly induced inflammatory mediators in the serum and a concomitant increase of immune cells in the blood and spleen of WT mice. Furthermore, it induced myocardial pattern recognition receptors and pro-inflammatory cytokines peaking 2 h after priming and a continuous increase of IL-10. 16 h after pre-conditioning, myocardial ischemia was induced for 1 h. Infarct size determined after 24 h of I/R was reduced by 75 % due to pre-conditioning with 1668-thioate but not in the other groups. During reperfusion, cytokine expression in 1668-thioate primed mice increased further with IL-10 exceeding the other mediators by far. These changes were observed neither in animals pre-treated with 1612- or H154-thioate nor in TLR9-deficient mice. The 1668-thioate-dependent increase of IL-10 was further supported by results of a micro-array analysis 3 h after begin of reperfusion. Block of IL-10 signaling increased I/R size and prevented influence of priming. In the group pre-treated with 1668-thioate, cardiac function was preserved 24 h, 14 days and 28 days after I/R, whereas animals without pre-conditioning exhibited impaired heart function 24 h and 14 days after I/R. The excessive 1668-thioate-dependent IL-10 up-regulation during pre-conditioning and after I/R seems to be the key factor for reducing infarct size and improving cardiac function. This is in agreement with the finding that IL-10 block prevents cardioprotection by pre-conditioning.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-013-0376-7) contains supplementary material, which is available to authorized users.

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

“…Velten et al () demonstrated that CpG‐ODN 1668 treatment attenuates cardiac hypertrophy following pressure overload by modifying the inflammatory response, thereby reducing cardiac growth and fibrosis as well as delaying the loss of cardiac function. Moreover, it has also been reported that the TLR9 activation induced by CpG‐ODN attenuates myocardial ischemia/reperfusion injury (Cao et al, ; Markowski et al, ). However, TLR9‐stimulation upon the onset of ischemia and subsequent reperfusion does not provide any benefit for cardiac ischemia/reperfusion injury (Ohm, Gao, et al, 2014).…”

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

“…Pharmacological preconditioning, however, may offer greater translational potential as dosages are easily controlled. We, and others, have demonstrated that pharmacological preconditioning via Toll-like receptor 9 (TLR9) holds great promise for use in prophylactic protection of the brain [12-14] as well as other organs against ischemic injury [15, 16]. …”

“…TLR9 mediated protection against ischemic injury, to date, has only been demonstrated with B-class CpGs [12-16], and although the protection is robust, increased systemic cytokine levels may restrict their use as clinical therapeutics. The A-class CpGs, with their minimal induction of systemic cytokines, may provide a safer alternative for prophylactic protection if, despite their distinct immune modulation, they protect against ischemic injury.…”

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

“…Several studies have reported a benefit of CpG-ODN in sepsis and cardiac function after I/R [12][13][14][15]. However, recent studies have demonstrated that TLR9 could be a therapeutic target for reducing myocardial I/R injury.…”