title: Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response.
abstract: BACKGROUND
  Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation.
  
  
  METHODS
  We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro and on the development of atherosclerosis using low-density lipoprotein receptor-deficient (Ldlr-/-) mice in vivo.
  
  
  RESULTS
  We show that Clec4e is expressed within human and mouse atherosclerotic lesions and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum stress response, leading to the induction of proinflammatory mediators and growth factors. Chop and Ire1a deficiencies significantly limit Clec4e-dependent effects, whereas Atf3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of Ldlr-/-mice with Clec4e-/-bone marrow reduces lipid accumulation, endoplasmic reticulum stress, and macrophage inflammation and proliferation within the developing arterial lesions and significantly limits atherosclerosis.
  
  
  CONCLUSIONS
  Our results identify a nonredundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis and suggest that it may play similar roles in other chronic inflammatory diseases.
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Marc
authors: M
authors: Clément
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Gemma
authors: G
authors: Basatemur
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Leanne
authors: L
authors: Masters
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Lauren
authors: L
authors: Baker
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Patrick
authors: P
authors: Bruneval
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Takao
authors: T
authors: Iwawaki
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Manfred
authors: M
authors: Kneilling
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Sho
authors: S
authors: Yamasaki
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).
authors: Jane
authors: J
authors: Goodall
authors: From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.). zm255@medchl.cam.ac.uk.
authors: Ziad
authors: Z
authors: Mallat
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C482593:CLEC4D protein, human; C113583:Clecsf8 protein, mouse; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL
keywords: atherosclerosis; cell proliferation; inflammation; necrosis