Role of MIF in myocardial ischaemia and infarction: insight from recent clinical and experimental findings

Abstract

First discovered in 1966 as an inflammatory cytokine, MIF (macrophage migration inhibitory factor) has been extensively studied for its pivotal role in a variety of inflammatory diseases, including rheumatoid arthritis and atherosclerosis. Although initial studies over a decade ago reported increases in circulating MIF levels following acute MI (myocardial infarction), the dynamic changes in MIF and its pathophysiological significance following MI have been unknown until recently. In the present review, we summarize recent experimental and clinical studies examining the diverse functions of MIF across the spectrum of acute MI from brief ischaemia to post-infarct healing. Following an acute ischaemic insult, MIF is rapidly released from jeopardized cardiomyocytes, followed by a persistent MIF production and release from activated immune cells, resulting in a sustained increase in circulating levels of MIF. Recent studies have documented two distinct actions of MIF following acute MI. In the supra-acute phase of ischaemia, MIF mediates cardioprotection via several distinct mechanisms, including metabolic activation, apoptosis suppression and antioxidative stress. In prolonged myocardial ischaemia, however, MIF promotes inflammatory responses with largely detrimental effects on cardiac function and remodelling. The pro-inflammatory properties of MIF are complex and involve MIF derived from cardiac and immune cells contributing sequentially to the innate immune response evoked by MI. Emerging evidence on the role of MIF in myocardial ischaemia and infarction highlights a significant potential for the clinical use of MIF agonists or antagonists and as a unique cardiac biomarker.

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…Previous studies demonstrated that following MI, MIF is immediately released from injured cardiomyocytes, providing predominately protective properties through its receptor, CD74, and its antioxidant capacity 27, 59, 60. In contrast, a second delayed wave of MIF derived from infiltrating immune cells contributes to aggravation of cardiac function and adverse cardiac remodeling, presumably mainly through CXCR2 and CXCR4 59.…”

“…In contrast, a second delayed wave of MIF derived from infiltrating immune cells contributes to aggravation of cardiac function and adverse cardiac remodeling, presumably mainly through CXCR2 and CXCR4 59. The recently discovered soluble CD74 ectodomain (sCD74) fragment expands the understanding about the complex interaction within the MIF protein family and necessitates to understand its role within the MIF/receptor network.…”

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

“…In the initial phase of ischemia, MIF promotes metabolic adaptation and recovery. With prolonged ischemia and myonecrosis, MIF’s proinflammatory actions supervene, resulting in detrimental effects on contractility, functional recovery, and ventricular remodeling [96]. …”

Plasma Macrophage Migration Inhibitor Factor Is Elevated in Response to Myocardial Ischemia

“…MIF has a range of actions, including metabolic regulation and modulation of inflammatory responses, and plays an important role in cardiovascular disease (CVD) . MIF is known to play a significant role in AMI and ischemia/reperfusion injury . Previous clinical studies by other groups reported an increase in plasma MIF levels in patients with AMI 4 to 6 hours after admission .…”