title: Apolipoprotein E induces antiinflammatory phenotype in macrophages.
abstract: OBJECTIVE
  Apolipoprotein E (apoE) exerts potent antiinflammatory effects. Here, we investigated the effect of apoE on the functional phenotype of macrophages.
  
  
  RESULTS
  Human apoE receptors very-low-density lipoprotein receptor (VLDL-R) and apoE receptor-2 (apoER2) were stably expressed in RAW264.7 mouse macrophages. In these cells, apoE downregulated markers of the proinflammatory M1 phenotype (inducible nitric oxide synthase, interleukin [IL]-12, macrophage inflammatory protein-1α) but upregulated markers of the antiinflammatory M2 phenotype (arginase I, SOCS3, IL-1 receptor antagonist [IL-1RA]). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis), as well as poly(I:C)- or interferon-γ-induced production of proinflammatory cytokines; cyclooxygenase-2 expression; and activation of nuclear factor-κB, IκB, and STAT1, were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of the M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice but not wild-type or low-density lipoprotein receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38 mitogen-activated protein kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38 mitogen-activated protein kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE-/- mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels, and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression).
  
  
  CONCLUSIONS
  ApoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the proinflammatory M1 to the antiinflammatory M2 phenotype. This effect may represent a novel antiinflammatory activity of apoE.
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, and Leibniz-Institute for Arteriosclerosis Research, University of Münster, Albert Schweizer Strasse 33, 48129 Münster, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baitsch
authors.forename: Hans H
authors.initials: HH
authors.lastname: Bock
authors.forename: Thomas
authors.initials: T
authors.lastname: Engel
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Horst
authors.initials: H
authors.lastname: Robenek
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D005260:Female; D005838:Genotype; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D026502:LDL-Receptor Related Proteins; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C