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Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.

Shamshiev AT, Ampenberger F, Ernst B, Rohrer L, Marsland BJ, Kopf M - J. Exp. Med. (2007)

Bottom Line: Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland.

ABSTRACT
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.

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BMDCs generated from HFCD-fed apoE−/− mice and splenic DCs from 5-wk-old apoE−/− mice exhibit normal responses upon TLR stimulation. (A) C57BL/6 (B6) and apoE−/− mice were fed HFCD for 12 wk, and BM cells were pooled from two mice for each group, and BMDCs were generated in GM-CSF–containing media, as described in the Materials and methods. At day 9 of culture, DCs were stimulated with the indicated doses of CpG or LPS for 6 h, followed by surface and intracellular staining. The percentages of CD11c+ and IL-12p40+ cells for each BMDC culture are shown. Similar results were obtained with poly(I:C)-stimulated cells and intracellular staining for IL-6 and TNF-α. (B) Splenic DCs were purified from C57BL/6 (B6) and apoE−/− mice at 5 wk of age and stimulated with CpG for 6 h, followed by surface and intracellular staining. IL-12p40 production was analyzed in CD8α+ or CD8α− CD11c+ DC subsets. The percentages of IL-12p40+ cells for each individual mouse are shown (n = 3).
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fig6: BMDCs generated from HFCD-fed apoE−/− mice and splenic DCs from 5-wk-old apoE−/− mice exhibit normal responses upon TLR stimulation. (A) C57BL/6 (B6) and apoE−/− mice were fed HFCD for 12 wk, and BM cells were pooled from two mice for each group, and BMDCs were generated in GM-CSF–containing media, as described in the Materials and methods. At day 9 of culture, DCs were stimulated with the indicated doses of CpG or LPS for 6 h, followed by surface and intracellular staining. The percentages of CD11c+ and IL-12p40+ cells for each BMDC culture are shown. Similar results were obtained with poly(I:C)-stimulated cells and intracellular staining for IL-6 and TNF-α. (B) Splenic DCs were purified from C57BL/6 (B6) and apoE−/− mice at 5 wk of age and stimulated with CpG for 6 h, followed by surface and intracellular staining. IL-12p40 production was analyzed in CD8α+ or CD8α− CD11c+ DC subsets. The percentages of IL-12p40+ cells for each individual mouse are shown (n = 3).

Mentions: We next used two strategies to assess whether the impairment of DC maturation and cytokine production was caused by dyslipidemia or simply associated with the absence of apoE. First, we generated BM-derived DCs (BMDCs), which are of myeloid origin (23), from chow diet– or HFCD-fed C57BL/6 or apoE−/− mice and stimulated them with TLR ligands. All BMDCs responded comparably to LPS, CpG, and poly(I:C), as determined by surface expression of CD40, CD80, CD86, MHC class II, and intracellular staining for IL-12p40, IL-6, and TNF-α (Fig. 6 A and not depicted). Second, we isolated splenic DCs from apoE−/− mice at 5 wk of age, i.e., before they had developed severe dyslipidemia. The response of splenic CD8α− DCs isolated from apoE−/− mice at 5 wk of age was similar to that of C57BL/6 controls, as shown by intracellular staining for IL-12p40 and surface staining for CD40 and CD80 (Fig. 6 B and not depicted). These results demonstrated that the apoE−/− CD8α− DCs were not intrinsically defective because of lack of apoE, and that the impaired response to TLR ligands was likely mediated by dyslipidemia.


Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.

Shamshiev AT, Ampenberger F, Ernst B, Rohrer L, Marsland BJ, Kopf M - J. Exp. Med. (2007)

BMDCs generated from HFCD-fed apoE−/− mice and splenic DCs from 5-wk-old apoE−/− mice exhibit normal responses upon TLR stimulation. (A) C57BL/6 (B6) and apoE−/− mice were fed HFCD for 12 wk, and BM cells were pooled from two mice for each group, and BMDCs were generated in GM-CSF–containing media, as described in the Materials and methods. At day 9 of culture, DCs were stimulated with the indicated doses of CpG or LPS for 6 h, followed by surface and intracellular staining. The percentages of CD11c+ and IL-12p40+ cells for each BMDC culture are shown. Similar results were obtained with poly(I:C)-stimulated cells and intracellular staining for IL-6 and TNF-α. (B) Splenic DCs were purified from C57BL/6 (B6) and apoE−/− mice at 5 wk of age and stimulated with CpG for 6 h, followed by surface and intracellular staining. IL-12p40 production was analyzed in CD8α+ or CD8α− CD11c+ DC subsets. The percentages of IL-12p40+ cells for each individual mouse are shown (n = 3).
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fig6: BMDCs generated from HFCD-fed apoE−/− mice and splenic DCs from 5-wk-old apoE−/− mice exhibit normal responses upon TLR stimulation. (A) C57BL/6 (B6) and apoE−/− mice were fed HFCD for 12 wk, and BM cells were pooled from two mice for each group, and BMDCs were generated in GM-CSF–containing media, as described in the Materials and methods. At day 9 of culture, DCs were stimulated with the indicated doses of CpG or LPS for 6 h, followed by surface and intracellular staining. The percentages of CD11c+ and IL-12p40+ cells for each BMDC culture are shown. Similar results were obtained with poly(I:C)-stimulated cells and intracellular staining for IL-6 and TNF-α. (B) Splenic DCs were purified from C57BL/6 (B6) and apoE−/− mice at 5 wk of age and stimulated with CpG for 6 h, followed by surface and intracellular staining. IL-12p40 production was analyzed in CD8α+ or CD8α− CD11c+ DC subsets. The percentages of IL-12p40+ cells for each individual mouse are shown (n = 3).
Mentions: We next used two strategies to assess whether the impairment of DC maturation and cytokine production was caused by dyslipidemia or simply associated with the absence of apoE. First, we generated BM-derived DCs (BMDCs), which are of myeloid origin (23), from chow diet– or HFCD-fed C57BL/6 or apoE−/− mice and stimulated them with TLR ligands. All BMDCs responded comparably to LPS, CpG, and poly(I:C), as determined by surface expression of CD40, CD80, CD86, MHC class II, and intracellular staining for IL-12p40, IL-6, and TNF-α (Fig. 6 A and not depicted). Second, we isolated splenic DCs from apoE−/− mice at 5 wk of age, i.e., before they had developed severe dyslipidemia. The response of splenic CD8α− DCs isolated from apoE−/− mice at 5 wk of age was similar to that of C57BL/6 controls, as shown by intracellular staining for IL-12p40 and surface staining for CD40 and CD80 (Fig. 6 B and not depicted). These results demonstrated that the apoE−/− CD8α− DCs were not intrinsically defective because of lack of apoE, and that the impaired response to TLR ligands was likely mediated by dyslipidemia.

Bottom Line: Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus