title: The cardiac maladaptive ATF3-dependent cross-talk between cardiomyocytes and macrophages is mediated by the IFNγ-CXCL10-CXCR3 axis.
abstract: BACKGROUND
  Pressure overload induces adaptive and maladaptive cardiac remodeling processes in the heart. Part of the maladaptive process is the cross-talk between cardiomyocytes and macrophages which is dependent on the function of the Activating Transcription Factor 3, ATF3. Yet, the molecular mechanism involved in cardiomyocytes-macrophages communication leading to macrophages recruitment to the heart and cardiac maladaptive remodeling is currently unknown.
  
  
  RESULTS
  Isolated peritoneal macrophages from either wild type or ATF3-KO mice were cultured in serum free medium to collect conditioned medium (CM). CM was used to probe an antibody cytokine/chemokine array. The interferon γ induced protein 10kDa, CXCL10, was found to be enriched in wild type macrophages CM. Wild type cardiomyocytes treated with CXCL10 in vitro, resulted in significant increase in cell volume as compared to ATF3-KO cardiomyocytes. In vivo, pressure overload was induced by phenylephrine (PE) infusion using micro-osmotic pumps. Consistently, CXCL11 (CXCL10 competitive agonist) and CXCL10 receptor antagonist (AMG487) attenuated PE-dependent maladaptive cardiac remodeling. Significantly, we show that the expression of the CXCL10 receptor, CXCR3, is suppressed in cardiomyocytes and macrophages derived from ATF3-KO mice. CXCR3 is positively regulated by ATF3 through an ATF3 transcription response element found in its proximal promoter. Finally, mice lacking CXCR3 display a significant reduction of cardiac remodeling processes following PE infusion.
  
  
  CONCLUSIONS
  Chronic PE infusion results in a unique cardiomyocytes-macrophages cross-talk that is mediated by IFNγ. Subsequently, macrophages that are recruited to the heart secrete CXCL10 resulting in maladaptive cardiac remodeling mediated by the CXCR3 receptor. ATF3-KO mice escape from PE-dependent maladaptive cardiac remodeling by suppressing the IFNγ-CXCL10-CXCR3 axis at multiple levels.
authors.affiliation: Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Koren
authors.affiliation: Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: U
authors.initials: U
authors.lastname: Barash
authors.affiliation: Department of Immunology, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Zohar
authors.affiliation: Department of Immunology, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Karin
authors.affiliation: Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: aronheim@tx.technion.ac.il.
authors.forename: A
authors.initials: A
authors.lastname: Aronheim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D007371:Interferon-gamma
keywords: ATF3; Cardiac remodeling; Cardiomyocytes; Macrophages; Phenylephrine; Pressure overload