Article: article from journal or magazin.
Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.
Journal of Experimental Medicine
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.
Adoptive Transfer, Animals, Antigens, CD8, Apolipoproteins E/genetics, Cytokines/metabolism, Dendritic Cells/immunology, Dendritic Cells/metabolism, Dyslipidemias/immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation/immunology, Leishmania major/immunology, Leishmaniasis, Cutaneous/immunology, Lipid Peroxidation/immunology, Lipoproteins, LDL/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Polymerase Chain Reaction, Th1 Cells/immunology, Toll-Like Receptors/immunology, Toll-Like Receptors/metabolism
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