Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.
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-alpha, as well as up-regulation of costimulatory molecules by CD8alpha(-) DCs, but not by CD8alpha(+) 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 CD8alpha(-) myeloid DCs and inhibit NF-kappaB 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.
Shamshiev
Abdijapar T
AT
Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland.
Ampenberger
Franziska
F
Ernst
Bettina
B
Rohrer
Lucia
L
Marsland
Benjamin J
BJ
Kopf
Manfred
M
D019264:Adoptive Transfer; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D016827:CD8 Antigens; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D050171:Dyslipidemias / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D015227:Lipid Peroxidation / Q000276:immunology; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
D001057:Apolipoproteins E; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines; D008077:Lipoproteins, LDL; D051193:Toll-Like Receptors; C099252:oxidized low density lipoprotein