Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis

Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil ext...

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Veröffentlicht in:	Circulation (New York, N.Y.) Jg. 125; H. 13; S. 1673
Hauptverfasser:	Döring, Yvonne, Manthey, Helga D, Drechsler, Maik, Lievens, Dirk, Megens, Remco T A, Soehnlein, Oliver, Busch, Martin, Manca, Marco, Koenen, Rory R, Pelisek, Jaroslav, Daemen, Mat J, Lutgens, Esther, Zenke, Martin, Binder, Christoph J, Weber, Christian, Zernecke, Alma
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 03.04.2012
Schlagworte:	Animals Atherosclerosis - genetics Atherosclerosis - immunology Atherosclerosis - metabolism Autoantigens - genetics Autoantigens - immunology Carotid Stenosis - genetics Carotid Stenosis - immunology Carotid Stenosis - metabolism Dendritic Cells - immunology Dendritic Cells - metabolism DNA - genetics DNA - immunology Female Humans Mice Mice, Inbred C57BL Mice, Knockout Proteins - genetics Proteins - immunology
ISSN:	1524-4539, 1524-4539
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Abstract	Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive. Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-α treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis. Self-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.
AbstractList	Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive. Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-α treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis. Self-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets. Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive.BACKGROUNDInflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive.Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-α treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.METHODS AND RESULTSHere we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-α treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.Self-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.CONCLUSIONSSelf-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.
Author	Koenen, Rory R Busch, Martin Drechsler, Maik Megens, Remco T A Zenke, Martin Binder, Christoph J Weber, Christian Soehnlein, Oliver Lievens, Dirk Pelisek, Jaroslav Lutgens, Esther Döring, Yvonne Zernecke, Alma Manthey, Helga D Manca, Marco Daemen, Mat J
Author_xml	– sequence: 1 givenname: Yvonne surname: Döring fullname: Döring, Yvonne organization: Rudolf Virchow Center, DFG Research Center for Experimental Medicine, University of Würzburg, Josef-Schneider Strasse 2, Würzburg, Germany – sequence: 2 givenname: Helga D surname: Manthey fullname: Manthey, Helga D – sequence: 3 givenname: Maik surname: Drechsler fullname: Drechsler, Maik – sequence: 4 givenname: Dirk surname: Lievens fullname: Lievens, Dirk – sequence: 5 givenname: Remco T A surname: Megens fullname: Megens, Remco T A – sequence: 6 givenname: Oliver surname: Soehnlein fullname: Soehnlein, Oliver – sequence: 7 givenname: Martin surname: Busch fullname: Busch, Martin – sequence: 8 givenname: Marco surname: Manca fullname: Manca, Marco – sequence: 9 givenname: Rory R surname: Koenen fullname: Koenen, Rory R – sequence: 10 givenname: Jaroslav surname: Pelisek fullname: Pelisek, Jaroslav – sequence: 11 givenname: Mat J surname: Daemen fullname: Daemen, Mat J – sequence: 12 givenname: Esther surname: Lutgens fullname: Lutgens, Esther – sequence: 13 givenname: Martin surname: Zenke fullname: Zenke, Martin – sequence: 14 givenname: Christoph J surname: Binder fullname: Binder, Christoph J – sequence: 15 givenname: Christian surname: Weber fullname: Weber, Christian – sequence: 16 givenname: Alma surname: Zernecke fullname: Zernecke, Alma
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/22388324$$D View this record in MEDLINE/PubMed
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Snippet	Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I...
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SubjectTerms	Animals Atherosclerosis - genetics Atherosclerosis - immunology Atherosclerosis - metabolism Autoantigens - genetics Autoantigens - immunology Carotid Stenosis - genetics Carotid Stenosis - immunology Carotid Stenosis - metabolism Dendritic Cells - immunology Dendritic Cells - metabolism DNA - genetics DNA - immunology Female Humans Mice Mice, Inbred C57BL Mice, Knockout Proteins - genetics Proteins - immunology
Title	Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis
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