Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2X<sub>7</sub>R/NLRP3 inflammasome.
Wu. Yan Y; Zhang. Yacheng Y; Zhang. Jie J; Zhai. Tingting T; Hu. Jingping J; Luo. Hairong H; Zhou. Haiyan H; Zhang. Qinghai Q; Zhou. Zhiguang Z; Liu. Feng F
Key Findings
- Cathelicidin levels rise in the heart during ischemia‑reperfusion and are mostly produced by infiltrating neutrophils.
- Mice lacking cathelicidin (Camp knockout) have smaller heart infarcts and lower blood troponin I after injury.
- Giving extra cathelicidin (CRAMP in mice, LL‑37 in human cells) before injury worsens damage, an effect blocked by inhibiting TLR4, P2X7R, or NLRP3.
- LL‑37 stimulates human neutrophils to release IL‑1β via the same inflammatory pathways.
Practical Outcomes
- For self‑experimenters, this study warns that boosting LL‑37 (e.g., through supplements or therapies that raise cathelicidin) could increase heart injury risk if a heart attack or similar ischemic event occurs. It suggests avoiding strategies that aim to raise LL‑37 levels for general health unless you have strong evidence of safety. Currently, there is no actionable protocol to use LL‑37 for performance or longevity; the peptide appears more harmful than beneficial in the context of heart stress.
Summary
In mice, the natural antimicrobial peptide cathelicidin (LL‑37 in humans) makes heart damage worse after a temporary blockage of blood flow. The peptide comes mainly from neutrophils (a type of white blood cell) that rush into the heart, and it triggers strong inflammation through TLR4 and the P2X7/NLRP3 inflammasome, leading to more cell death and higher heart‑damage markers.
Abstract
The antimicrobial peptide cathelicidin (Camp) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. 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 P2X<sub>7</sub>R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X<sub>7</sub>R, 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 P2X<sub>7</sub>R/NLRP3 inflammasome. 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 P2X<sub>7</sub>R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury.
Study Information
pubmed
2020
2020-01-23T00:00:00.000Z
10.1016/j.yjmcc.2019.12.011
35
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