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IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult.
- Source :
-
European heart journal [Eur Heart J] 2018 Jan 01; Vol. 39 (1), pp. 60-69. - Publication Year :
- 2018
-
Abstract
- Aims: Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult.<br />Methods and Results: Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis.<br />Conclusion: Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Cytokines metabolism
Fibrosis metabolism
Heart drug effects
Humans
Inflammasomes drug effects
Inflammasomes metabolism
Isoproterenol pharmacology
Male
Mice
Mice, Inbred C57BL
Myocardium immunology
Stress, Physiological drug effects
Stress, Physiological physiology
Adrenergic beta-Agonists pharmacology
Inflammation metabolism
Interleukin-18 metabolism
Myocardium metabolism
Receptors, Adrenergic, beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9645
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- European heart journal
- Publication Type :
- Academic Journal
- Accession number :
- 28549109
- Full Text :
- https://doi.org/10.1093/eurheartj/ehx261