title: Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection.
abstract: BACKGROUND
  Intraplaque hemorrhage (IPH) drives atherosclerosis through the dual metabolic stresses of cholesterol-enriched erythrocyte membranes and pro-oxidant heme/iron. When clearing tissue hemorrhage, macrophages are typically seen storing either iron or lipid. We have recently defined hemorrhage-associated macrophages (HA-mac) as a plaque macrophage population that responds adaptively to IPH.
  
  
  OBJECTIVE
  This study aimed to define the key transcription factor(s) involved in HO-1 induction by heme.
  
  
  RESULTS
  To address this question, we used microarray analysis and transfection with siRNA and plasmids. To maintain physiological relevance, we focused on human blood-derived monocytes. We found that heme stimulates monocytes through induction of activating transcription factor 1 (ATF-1). ATF-1 coinduces heme oxygenase-1 (HO-1) and Liver X receptor beta (LXR-β). Heme-induced HO-1 and LXR-β were suppressed by knockdown of ATF-1, and HO-1 and LXR-β were induced by ATF-1 transfection. ATF-1 required phosphorylation for full functional activity. Expression of LXR-β in turn led to induction of other genes central to cholesterol efflux, such as LXR-α and ABCA1. This heme-directed state was distinct from known macrophage states (M1, M2, Mox) and, following the same format, we have designated them Mhem.
  
  
  CONCLUSIONS
  These results show that ATF-1 mediates HO-1 induction by heme and drives macrophage adaptation to intraplaque hemorrhage. Our definition of an ATF-1-mediated pathway for linked protection from foam cell formation and oxidant stress may have therapeutic potential.
authors: Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, UK. joseph.boyle@imperial.ac.uk
authors: Joseph J
authors: JJ
authors: Boyle
authors: Michael
authors: M
authors: Johns
authors: Theresa
authors: T
authors: Kampfer
authors: Aivi T
authors: AT
authors: Nguyen
authors: Laurence
authors: L
authors: Game
authors: Dominik J
authors: DJ
authors: Schaer
authors: Justin C
authors: JC
authors: Mason
authors: Dorian O
authors: DO
authors: Haskard
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D005487:Foam Cells / Q000473:pathology*; D006418:Heme / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006470:Hemorrhage / Q000473:pathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D058226:Plaque, Atherosclerotic / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D051697:Activating Transcription Factor 1; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D006418:Heme; D007501:Iron; D051547:Heme Oxygenase-1