title: Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4.
abstract: Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia- and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4(def) mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Si
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Howard H
authors.initials: HH
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: H Shaw
authors.initials: HS
authors.lastname: Warren
authors.forename: David E
authors.initials: DE
authors.lastname: Sosnovik
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018834:Chaperonin 60 / Q000276:immunology*; D007113:Immunity, Innate; D007249:Inflammation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000276:immunology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D018834:Chaperonin 60; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; D020169:Caspases