title: Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion.
abstract: OBJECTIVE
  Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells.
  
  
  RESULTS
  Using bone marrow transplantation, we generated chimeric mice with Cxcr2(-/-) bone marrow-derived inflammatory cells and wild-type (wt) resident cells (wt/Cxcr2(-/-)), Cxcr2(-/-) cardiomyocytes and wt bone marrow-derived cells (Cxcr2(-/-)/wt), and wt controls reconstituted with wt bone marrow (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial ischemia and reperfusion. 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. Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner.
  
  
  CONCLUSIONS
  The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2. Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered when developing novel therapeutic strategies to treat myocardial infarction.
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Isabella
authors.initials: I
authors.lastname: Kanzler
authors.forename: Simone
authors.initials: S
authors.lastname: Konschalla
authors.forename: Andreas
authors.initials: A
authors.lastname: Kroh
authors.forename: Sakine
authors.initials: S
authors.lastname: Simsekyilmaz
authors.forename: Tolga Taha
authors.initials: TT
authors.lastname: Sönmez
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D006339:Heart Rate; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D018183:Transplantation Chimera; D014463:Ultrasonography
chemical_list: D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D023063:Receptors, Interleukin-8B; C045084:invariant chain; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: CXCR2 receptors; ischemia-reperfusion injury; macrophage migration-inhibitory factors; myocardial infarction