Abstract
ObjectiveRecent studies indicate that the innate immune system is not only triggered by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As triggers for the innate immune NLRP3 inflammasome protein complex appear to overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NLRP3 inflammasome is involved in IPC and acute I/R injury of the heart.Principal FindingsBaseline cardiac performance and acute I/R injury were investigated in isolated, Langendorff-perfused hearts from wild-type (WT), ASC−/− and NLRP3−/− mice. Deletion of NLRP3 inflammasome components ASC−/− or NLRP3−/− did not affect baseline performance. The deletions exacerbated I/R-induced mechanical dysfunction, but were without effect on I/R-induced cell death. When subjected to IPC, WT and ASC−/− hearts were protected against I/R injury (improved function and less cell death). However, IPC did not protect NLRP3−/− hearts against I/R injury. NLRP3−/− hearts had significantly decreased cardiac IL-6 levels with a trend towards lower IL-1β levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 and/or IL-1β signaling. Subsequent experiments showed that neutralising IL-6 using an antibody against IL-6 abrogated IPC in WT hearts. However, inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) did not abrogate IPC in WT hearts. Analysis of survival kinases after IPC demonstrated decreased STAT3 expression in NLRP3−/− hearts when compared to WT hearts.ConclusionsThe data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism.
Highlights
The innate immune system is the first line of defence against stress signals such as exogenous pathogen-associated molecular patterns (PAMPs) and pollutants
The data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of ischemic preconditioning (IPC) in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism
In this study we have investigated whether the NLRP3 inflammasome is involved in acute cardiac I/R injury and IPC, and whether specific inflammatory pathways that are affected by ablation of constituents (NLRP3 or ASC) of the assembled NLRP3 inflammasome are involved in observed changes in I/R and IPC
Summary
The innate immune system is the first line of defence against stress signals such as exogenous pathogen-associated molecular patterns (PAMPs) and pollutants. Recent data have demonstrated that the innate immune system is activated by ischemia and necrosis through endogenous danger-associated molecular patterns (DAMPs), the so-called sterile inflammatory response [1]. Such DAMPs may entail uric acid, adenosine, ATP, heat shock protein, HMGB1, DNA, or myosin released by damaged cells [1,2,3]. In the current work we examine to what extent the NLRP3 inflammasome, a specific part of the innate immune system, affects acute I/R and IPC cardiac physiology Such interrelationships between hypoxia, IPC and inflammation are well documented for other, non-inflammasome, parts of the immune system, where hypoxia-induced hypoxia-inducible transcription factor HIF modulates inflammation and IPC through adenosine and NF-kB signaling [7], [8]
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