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Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischemia/reperfusion injury in mice
Juma El-Awaisi, … , Nigel E. Drury, Neena Kalia
Juma El-Awaisi, … , Nigel E. Drury, Neena Kalia
Published February 3, 2022
Citation Information: JCI Insight. 2022;7(5):e155236. https://doi.org/10.1172/jci.insight.155236.
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Research Article Aging Inflammation

Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischemia/reperfusion injury in mice

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Abstract

Following myocardial infarction (MI), elderly patients have a poorer prognosis than younger patients, which may be linked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), a newly discovered proinflammatory member of the IL-1 superfamily, may mediate this injury, but its role in the injured heart is currently not known. We first demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischemia/reperfusion-injured (IR-injured) mouse hearts and, interestingly, noted that expression of both increased with aging. 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 with 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 population.

Authors

Juma El-Awaisi, Dean P.J. Kavanagh, Marco R. Rink, Chris J. Weston, Nigel E. Drury, Neena Kalia

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Figure 6

Age increases thromboinflammatory disturbances within the healthy and IR-injured beating heart coronary microcirculation in vivo, which can be prevented in both age groups by IL-36R inhibition.

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Age increases thromboinflammatory disturbances within the healthy and IR...
An IL-36Ra (15 μg/mouse) was injected intra-arterially at 10 minutes prereperfusion and 60 minutes postreperfusion in adult and aged mice. (A) Representative intravital images of the beating heart showing adherent neutrophils (green) and platelets (red) in the coronary microcirculation at 60 and 120 minutes in sham hearts or 60 and 120 minutes postreperfusion in injured hearts. Adherent neutrophils (green) and platelet microthrombi (red) are primarily within coronary capillaries in injured hearts. Intensely fluorescent green areas in aged IR-injured hearts correspond to medium-sized blood vessels that have become delineated by the presence of a substantial number of adherent neutrophils. Quantitative analysis of the intravital data for adherent neutrophils in (B) adult and (C) aged IR-injured hearts and the AUC for (D) adherent neutrophils and (E) platelets over a time course of 150 minutes. Scale bar indicates 100 μm. Adult sham — n = 5/group; adult IRI — n = 6/group; adult IRI + IL-36Ra — n = 5/group; aged sham — n = 7/group; aged IRI — n = 5/group; aged IRI + IL-36Ra — n = 8/group. *P = 0.0339, **P = 0.0014, ***P = 0.0003, ****P < 0.0001 as determined using a 1-way ANOVA followed by a Tukey’s post hoc test.

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