Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts.

Svenja Voss,Michael Schwarzl,Christian Meyer,Diana Lindner,Stefan Blankenberg,Katharina Scherschel,Benedikt Schrage,Evaldas Girdauskas,Svenja Warnke,Saskia Krüger,Dirk Westermann

doi:10.3390/biom9020038

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio-protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto-/paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.

Highlights

IntroductionThe acute interruption of blood flow to cardiac tissue leads to a demise of cardiomyocytes within the ischemic area [1,3]
Myocardial infarction (MI) remains one of the leading causes of death in Western society [1,2].The acute interruption of blood flow to cardiac tissue leads to a demise of cardiomyocytes within the ischemic area [1,3]
Since Mif but not Mif-2 was upregulated during acute MI, we further investigated different external stimuli to activate cardiomyocytes, cardiac fibroblasts and leukocytes detected as one cellular source of Mif within the left ventricular (LV) tissue

Summary

Introduction

The acute interruption of blood flow to cardiac tissue leads to a demise of cardiomyocytes within the ischemic area [1,3]. This, further triggers the infiltration of the infarcted heart by leukocytes, leading to local inflammatory processes [3,4,5]. Recruited leukocytes remove dead cells and cellular debris via phagocytosis. This cardiac inflammatory response is thereby essential for cardiac repair and promotes scar formation by deposition of extracellular matrix proteins. Aggravated cardiac inflammation can induce adverse tissue remodeling, which impairs contractile function and can lead to the development of heart failure [3,6,7,8,9]

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Discussion

Conclusion