Dyslipidemia inhibits Toll-like receptor–induced activation of CD8α-negative dendritic cells and protective Th1 type immunity (original) (raw)
Article| February 12 2007
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
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1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
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1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
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2Institute of Clinical Chemistry, University Hospital Zürich, 8057 Zürich, Switzerland
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1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
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1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
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Abdijapar T. Shamshiev
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
Franziska Ampenberger
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
Bettina Ernst
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
Lucia Rohrer
2Institute of Clinical Chemistry, University Hospital Zürich, 8057 Zürich, Switzerland
Benjamin J. Marsland
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
Manfred Kopf
1Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland
Abbreviations used: APC, allophycocyanin; BMDC, BM-derived DC; DLN, draining LN; HFCD, high-fat/cholesterol diet; HFD, high-fat diet; LDL, low-density lipoprotein; oxLDL, oxidized LDL; nLDL, native LDL; TBARS, thiobarbituric acid–reactive substrates; Tg, transgenic; TLR, Toll-like receptor; VLDL, very LDL.
Received: August 14 2006
Accepted: January 19 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (2): 441–452.
Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet–induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)–induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-α, as well as up-regulation of costimulatory molecules by CD8α− DCs, but not by CD8α+ DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8α− myeloid DCs and inhibit NF-κB nuclear translocation. These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell–mediated immunity.
The Rockefeller University Press
2007
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