Details

Autor(en) / Beteiligte

• Xiao, Han
• Li, Hao
• Wang, Jing-Jing
• Zhang, Jian-Shu
• Shen, Jing
• An, Xiang-Bo
• Zhang, Cong-Cong
• Wu, Ji-Min
• Song, Yao
• Wang, Xin-Yu
• Yu, Hai-Yi
• Deng, Xiang-Ning
• Li, Zi-Jian
• Xu, Ming
• Lu, Zhi-Zhen
• Du, Jie
• Gao, Wei
• Zhang, Ai-Hua
• Feng, Yue
• Zhang, You-Yi

Titel

IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult

Ist Teil von

• European heart journal, 2018-01, Vol.39 (1), p.60-69

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2018

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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. 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. 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.