TY - JOUR
T1 - Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2X7R/NLRP3 inflammasome
AU - Wu, Yan
AU - Zhang, Yacheng
AU - Zhang, Jie
AU - Zhai, Tingting
AU - Hu, Jingping
AU - Luo, Hairong
AU - Zhou, Haiyan
AU - Zhang, Qinghai
AU - Zhou, Zhiguang
AU - Liu, Feng
N1 - Funding Information:
We thank Dr. Hongliang Li at Collaborative Innovation Center of Model Animal Wuhan University, China for providing Tlr4 KO mice, Dr. Philipp E. Scherer at University of Texas Southwestern Medical Center , USA for providing Tlr4 fl/fl mice, and Dr. Jean-Sébastien Silvestre at INSERM UMRS 970, France for expert technical assistance. This work was supported by the National Natural Science Foundation of China (No. 81400352 and No. 81200580 ) and the National Institutes of Health , United States (R01 grant DK100697 ).
Funding Information:
We thank Dr. Hongliang Li at Collaborative Innovation Center of Model Animal Wuhan University, China for providing Tlr4 KO mice, Dr. Philipp E. Scherer at University of Texas Southwestern Medical Center, USA for providing Tlr4fl/fl mice, and Dr. Jean-S?bastien Silvestre at INSERM UMRS 970, France for expert technical assistance. This work was supported by the National Natural Science Foundation of China (No.81400352 and No.81200580) and the National Institutes of Health, United States (R01 grant DK100697). None declared.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/2
Y1 - 2020/2
N2 - Aims: The antimicrobial peptide cathelicidin (Camp) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. Methods and results: In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion. An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils. Knockout of Camp in mice reduced MI/R-induced myocardial inflammation, infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X7R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X7R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1β (a “first line” pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1β protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1β from human neutrophils via stimulating TLR4 signaling and P2X7R/NLRP3 inflammasome. Conclusions: Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X7R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury.
AB - Aims: The antimicrobial peptide cathelicidin (Camp) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. Methods and results: In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion. An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils. Knockout of Camp in mice reduced MI/R-induced myocardial inflammation, infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X7R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X7R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1β (a “first line” pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1β protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1β from human neutrophils via stimulating TLR4 signaling and P2X7R/NLRP3 inflammasome. Conclusions: Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X7R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury.
KW - Cathelicidin
KW - Ischemia/reperfusion
KW - NLRP3 inflammasome
KW - Neutrophils
KW - P2XR
KW - TLR4
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UR - http://www.scopus.com/inward/citedby.url?scp=85078249160&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2019.12.011
DO - 10.1016/j.yjmcc.2019.12.011
M3 - Article
C2 - 31982429
AN - SCOPUS:85078249160
VL - 139
SP - 75
EP - 86
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -