title: Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling.
abstract: OBJECTIVE
  Recent 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.
  
  
  RESULTS
  Baseline 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.
  
  
  CONCLUSIONS
  The 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.
authors: Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl
authors: Coert J
authors: CJ
authors: Zuurbier
authors: Willeke M C
authors: WM
authors: Jong
authors: Otto
authors: O
authors: Eerbeek
authors: Anneke
authors: A
authors: Koeman
authors: Wilco P
authors: WP
authors: Pulskens
authors: Loes M
authors: LM
authors: Butter
authors: Jaklien C
authors: JC
authors: Leemans
authors: Markus W
authors: MW
authors: Hollmann
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D007113:Immunity, Innate / Q000235:genetics; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse