Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischaemia-reperfusion injury in mice: ageing and the coronary microcirculation

Juma Elawaisi, Dean Kavanagh, Marco Rink, Chris Weston, Nigel Drury, Neena Kalia

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Abstract

Following myocardial infarction (MI), elderly patients have a poorer prognosis which may be linked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), a newly discovered pro-inflammatory member of the IL-1 superfamily, may mediate this injury but its role in the injured heart is currently not known. We firstly demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischaemia-reperfusion (IR) injured mouse hearts and, interestingly, noted that expression of both increased with ageing. An intravital model for imaging the adult and aged IR injured beating heart in real-time in vivo was used to demonstrate heightened basal and injury-induced neutrophil recruitment, and poorer blood flow, in the aged coronary microcirculation when compared to adult hearts. An IL-36R antagonist (IL-36Ra) decreased neutrophil recruitment, improved blood flow and reduced infarct size in both adult and aged mice. This may be mechanistically explained by attenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra treated mice. Our findings of an enhanced age-related coronary microcirculatory dysfunction in reperfused hearts may explain the poorer outcomes in elderly patients following MI. Since targeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly.
Original languageEnglish
JournalJCI Insight
Early online date3 Feb 2022
DOIs
Publication statusE-pub ahead of print - 3 Feb 2022

Keywords

  • Myocardial infarction
  • coronary microcirculation
  • ageing
  • ischaemia-reperfusion injury
  • neutrophils
  • platelets
  • interleukin-36

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