Interleukin-1 Receptor Type I Signaling Critically Regulates Infarct Healing and Cardiac Remodeling

Abstract

The proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI؊/؊ mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI ؊/؊ mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1␤ stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction. Infarct healing is dependent on induction of an inflammatory cascade that ultimately results in formation of a collagen-based scar.1 The healing response is closely intertwined with ventricular remodeling, a complex process that involves both the infarcted and noninfarcted myocardium resulting in dilation, hypertrophy, and enhanced sphericity of the ventricle. 2 The extent of remodeling after infarction is an important predictor of mortality and adverse outcome after infarction, 3,4 and depends on the size of the infarct and on the mechanical and structural characteristics of the healing wound. Inflammatory mediators may be critically involved in the pathogenesis of cardiac remodeling by modulating cell behavior in the infarcted heart and by regulating extracellular matrix metabolism. 5-7Interleukin (IL)-1 plays a central role in regulating inflammatory and fibrotic responses by inducing synthesis of proinflammatory mediators, by promoting leukocyte infiltration and activation, and by modulating fibroblast function. IL-1 binds to two distinct receptors on the cell membrane: the type I IL-1 receptor (IL-1RI) is sufficient to mediate all IL-1 actions, 8 whereas the type II receptor (IL-1RII) serves as a decoy target, 9 trapping and scavenging IL-1 molecules, 10 thus reducing IL-1 concentration available for interaction with the IL-1RI signa...

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

“…In models of acute myocardial infarction (AMI), genetic or pharmacological inhibition of IL-1 reduces LV dysfunction, limits the adverse remodeling process and has no effects on myocardial fibrosis, yet reduces mortality (18,20,(39)(40)(41)(42). There appear to be similarities and differences in the role of IL-1 in the ischemic and XRT-induced cardiomyopathy.…”

The immune system and cardiac repair

“…IL-1β stimulated MMP mRNA synthesis in wildtype, but not in IL-1RI null cardiac fibroblasts. The findings suggested that IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct and may play an essential role in the pathogenesis of post-infarction remodeling [162].…”

“…In contrast, another investigation suggested a protective role for IL-1 demonstrating that IL-1β neutralization in the acute phase of myocardial infarction resulted in increased occurrence of cardiac rupture and enhanced adverse remodeling [161]. Because IL-1 signals exclusively through the IL-1 receptor type I (IL-1RI) we have recently examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI −/− mice [162]. Following reperfused infarction IL-1RI null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…However, it is not clear what the endogenous ligand for TLR5 is in the damaged heart as its only known ligand is bacterial flagellin. Studies on IL-1R1 knockout mice have consistently shown beneficial effects on post-MI remodelling [59][60][61]. Only a few studies have investigated the role of NLRs in cardiac remodelling and different effects were observed depending on the cardiac injury model used.…”

“…Increased myocardial IL-1/ levels are observed with several cardiovascular pathologies including MI, cardiomyopathy, hypertension and myocarditis [84][85][86]. In studies using knockout mice, IL-1R1 deletion led to smaller infarcts, less inflammation and reduced cardiac dysfunction following MI [59][60][61].…”