Compartmentalized Protective and Detrimental Effects of Endogenous Macrophage Migration-Inhibitory Factor Mediated by CXCR2 in a Mouse Model of Myocardial Ischemia/Reperfusion

Abstract

Objectives Here we aimed to clarify the role of CXCR2 in the macrophage migration inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion (I/R). As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors including CD74 and CXCR2. In models of myocardial infarction (MI), MIF exerts both pro-inflammatory effects and protective effects in cardiomyocytes. Likewise, CXCR2 displays opposing effects in resident versus circulating cells. Approach and results Using bone marrow (BM) transplantation, we generated chimeric mice with CXCR2−/− BM-derived inflammatory cells and wild-type resident cells (wt/CXCR2−/−), with CXCR2−/− cardiomyocytes and wild-type BM-derived cells (CXCR2−/−/wt) and wild-type controls reconstituted with wild-type BM (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial I/R. Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2−/− mice but ameliorated functional parameters in CXCR2−/−/wt mice, as analyzed by echocardiography and Langendorff perfusion. Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or CXCR2 deficiency. Monocyte infiltration was blunted in wt/CXCR2−/− mice and reduced by MIF blockade in wt/wt and CXCR2−/−/wt mice. Moreover, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner. Conclusions The compartmentalized and opposing effects of MIF after myocardial I/R are largely mediated by CXCR2. Whereas MIF confers protective effects improving myocardial healing and function through CXCR2 in resident cells, complementing paracrine effects through CD74/AMPK, it exerts detrimental effects on CXCR2-bearing inflammatory cells, increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered, when developing novel therapeutic strategies to treat MI.

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

“…3,[63][64][65] For bone marrow transplantation, 10-weekold female Mif 2/2 (n=5) and C57Bl/6N (n=10) WT littermates were used as recipients and 10-week-old male Mif 2/2 (n=3) and C57Bl/6N…”

Role of macrophage migration inhibitory factor in age-related lung disease

“…Reciprocally, MIF can help stabilize HIF-1␣ and enhance its transcription (55,82,155). MIF chemotactic function has been implicated in atherosclerotic plaque formation and the recruitment of cells important for neovascularization, such as endothelial progenitor cells (54,75,125,130). Finally, MIF functions as a chemotactant for neutrophils, monocytes/macrophages, and lymphocytes to sites of injury.…”

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

“…In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33. MIF also signals through the chemokine receptors, C‐X‐C chemokine receptor (CXCR)2 and CXCR4,34 and has been found to exhibit compartmentalized protective and detrimental effects through CXCR2 receptor in a mouse model of myocardial ischemia/reperfusion 35. Whereas the C‐X‐C motif chemokine ligand 12/CXCR4 axis also has a double‐edged role in experimental MI, the contribution of the MIF/CXCR4 ligand/receptor axis has not yet been directly studied in the heart 36…”