Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction

J Mol Cell Cardiol. 2014 Apr:69:32-42. doi: 10.1016/j.yjmcc.2014.01.015. Epub 2014 Feb 5.

Abstract

Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators' expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissect the role of MIF derived from different cellular sources in post-MI cardiac remodelling, we generated chimeric mice with MIF deficiency either in bone marrow derived-cells (WT(KO)) or in somatic-cells (KO(WT)). Compared to WT and KO(WT) mice, WT(KO) mice had reduced rupture risk and ameliorated cardiac remodelling, associated with attenuated regional leukocyte infiltration and expression of inflammatory mediators. In contrast, KO(WT) mice had delayed healing and enhanced expression of M1 macrophage markers, but diminished expression of M2 markers during the early healing phase. In conclusion, global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation. Leukocyte-derived MIF promotes inflammatory responses after MI, whereas cardiac-derived MIF affects early but not ultimate healing process.

Keywords: Healing; Inflammation; Macrophage migration inhibitory factor; Myocardial infarction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Heart Rupture, Post-Infarction / immunology*
  • Heart Rupture, Post-Infarction / metabolism
  • Heart Rupture, Post-Infarction / pathology
  • Immunoenzyme Techniques
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Intramolecular Oxidoreductases / physiology*
  • Leukocytes / immunology*
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Macrophage Migration-Inhibitory Factors / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / immunology*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Phosphorylation
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Inflammation Mediators
  • Macrophage Migration-Inhibitory Factors
  • RNA, Messenger
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Intramolecular Oxidoreductases
  • Mif protein, mouse