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

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.

Dual-modal molecular imaging and therapeutic evaluation of coronary microvascular dysfunction using indocyanine green-doped targeted microbubbles

“…CMD mouse models were established using C57BL/6J mice, and the detailed steps are as follows. 28 Firstly, mice were anesthetized with avertin intraperitoneally. Then, they were intubated using a direct visual tracheal intubation puncture cannula, followed by connecting to a small animal ventilator to adjust the frequency and tidal volume.…”

Inflammation as the nexus: exploring the link between acute myocardial infarction and chronic obstructive pulmonary disease

“…As well as amplifying IL-1 effects, IL-36 is also a mediator of inflammation in its own right. Indeed, its critical role in psoriasis, equalling if not surpassing that of IL-1, is well established with emerging roles in Crohn disease and rheumatoid arthritis recently identified ( 130 – 132 ). Research into IL-36 as a pro-inflammatory cytokine in various inflammatory diseases is extensive, but studies in AMI or COPD are more recent.…”

The role of extracellular traps in ischemia reperfusion injury

“…Further, mCBS injection 5 min before and after cutaneous I/R can consistently and significantly increase the area of skin flap survival (124). IL-36 receptor antagonist (IL-36Ra), encoded by Il36rn, attenuates myocardial IRI though reducing neutrophil recruitment and improving blood flow in mice (181). Tanaka et al (129) found that in Il36rn -/mice, cutaneous I/R resulted in a significant delay in wound healing and increased inflammatory cell infiltration.…”