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CD1d-dependent activation of NKT cells aggravates atherosclerosis.

Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK, Berne GP - J. Exp. Med. (2004)

Bottom Line: Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response.Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta.Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

ABSTRACT
Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E-deficient (apoE-/-) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE-/- mice crossed with CD1d-/- (CD1d-/-apoE-/-) mice exhibited a 25% decrease in lesion size compared with apoE-/- mice. Administration of alpha-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE-/- mice, whereas it did not affect lesion size in apoE-/-CD1d-/- mice. Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.

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Systemic effects of αGalCer in apoE−/− mice. 5-wk-old apoE−/− mice were injected one, three, or five times, twice a week, with αGalCer or PBS. The first injection was i.v. (n = 6 for αGalCer and n = 5 for PBS) and the following ones i.p (n = 5 for αGalCer and n = 3 for PBS). Mice were killed 12 h after the last injection. (a) Serum levels of cytokines after one injection of αGalCer or PBS. In control (PBS) mice, levels of IFNγ, TNFα, and IL-6 were not detectable (nd). (b) Activated spleen T (CD69+TCRαβ+) and B (CD19+B7.2+) cells determined by flow cytometry. (c) IFNγ and IL-4 mRNA in spleens measured by quantitative real-time RT-PCR and normalized to β-actin mRNA after one, three, and five injections. The values for IFNγ are represented in a logarithmic scale. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice).
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fig3: Systemic effects of αGalCer in apoE−/− mice. 5-wk-old apoE−/− mice were injected one, three, or five times, twice a week, with αGalCer or PBS. The first injection was i.v. (n = 6 for αGalCer and n = 5 for PBS) and the following ones i.p (n = 5 for αGalCer and n = 3 for PBS). Mice were killed 12 h after the last injection. (a) Serum levels of cytokines after one injection of αGalCer or PBS. In control (PBS) mice, levels of IFNγ, TNFα, and IL-6 were not detectable (nd). (b) Activated spleen T (CD69+TCRαβ+) and B (CD19+B7.2+) cells determined by flow cytometry. (c) IFNγ and IL-4 mRNA in spleens measured by quantitative real-time RT-PCR and normalized to β-actin mRNA after one, three, and five injections. The values for IFNγ are represented in a logarithmic scale. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice).

Mentions: An early burst of inflammatory cytokines was detected in sera after an injection of αGalCer; both typical Th1 (IFNγ, TNFα, IL-2) and Th2 (IL-4, IL-5) cytokines were increased as well as IL-6 and MCP-1 (Fig. 3 a). However, neither IL-10, which has antiinflammatory and atheroprotective properties (18, 25), nor IL-12 was detected in any of the groups (not depicted). The increase was remarkable, e.g., 5,000-fold for IFNγ and 250-fold for MCP-1. Bystander activation of T and B cells was registered by an increased number of cells double positive for CD69/TCRβ and B7.2/CD19, respectively (Fig. 3 b). This early burst of cytokines might explain the increased expression of VCAM-1, which can be induced by proinflammatory cytokines, and I-Ab, which is induced by IFNγ. The increased levels of circulating MCP-1 might be significant for the exacerbated lesion development in αGalCer-treated mice, since this chemokine has important proatherogenic effects (21, 22). High levels of IL-6 could also have effects on atherosclerosis, since early lesions in apoE−/− mice are exacerbated by recombinant IL-6 (23). Elevated circulating IL-6 concentrations is correlated with increased risk of coronary and peripheral atherosclerosis in man (24). After repeated injections, serum levels of cytokines fell below the detection limit, and no signs of increased T or B cell activation could be detected anymore. Real-time RT-PCR analysis (see Supplemental Materials and Methods, available at http://www.jem.org/cgi/content/full/jem.20030997/DC1) of spleen mRNA confirmed the increase in IFNγ (85-fold) and IL-4 (25-fold) mRNA in mice injected once with αGalCer (Fig. 3 c) and demonstrated that increased IFNγ and IL-4 expression in the spleen was still detectable after repeated injections (Fig. 3 c).


CD1d-dependent activation of NKT cells aggravates atherosclerosis.

Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK, Berne GP - J. Exp. Med. (2004)

Systemic effects of αGalCer in apoE−/− mice. 5-wk-old apoE−/− mice were injected one, three, or five times, twice a week, with αGalCer or PBS. The first injection was i.v. (n = 6 for αGalCer and n = 5 for PBS) and the following ones i.p (n = 5 for αGalCer and n = 3 for PBS). Mice were killed 12 h after the last injection. (a) Serum levels of cytokines after one injection of αGalCer or PBS. In control (PBS) mice, levels of IFNγ, TNFα, and IL-6 were not detectable (nd). (b) Activated spleen T (CD69+TCRαβ+) and B (CD19+B7.2+) cells determined by flow cytometry. (c) IFNγ and IL-4 mRNA in spleens measured by quantitative real-time RT-PCR and normalized to β-actin mRNA after one, three, and five injections. The values for IFNγ are represented in a logarithmic scale. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice).
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Related In: Results  -  Collection

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fig3: Systemic effects of αGalCer in apoE−/− mice. 5-wk-old apoE−/− mice were injected one, three, or five times, twice a week, with αGalCer or PBS. The first injection was i.v. (n = 6 for αGalCer and n = 5 for PBS) and the following ones i.p (n = 5 for αGalCer and n = 3 for PBS). Mice were killed 12 h after the last injection. (a) Serum levels of cytokines after one injection of αGalCer or PBS. In control (PBS) mice, levels of IFNγ, TNFα, and IL-6 were not detectable (nd). (b) Activated spleen T (CD69+TCRαβ+) and B (CD19+B7.2+) cells determined by flow cytometry. (c) IFNγ and IL-4 mRNA in spleens measured by quantitative real-time RT-PCR and normalized to β-actin mRNA after one, three, and five injections. The values for IFNγ are represented in a logarithmic scale. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice).
Mentions: An early burst of inflammatory cytokines was detected in sera after an injection of αGalCer; both typical Th1 (IFNγ, TNFα, IL-2) and Th2 (IL-4, IL-5) cytokines were increased as well as IL-6 and MCP-1 (Fig. 3 a). However, neither IL-10, which has antiinflammatory and atheroprotective properties (18, 25), nor IL-12 was detected in any of the groups (not depicted). The increase was remarkable, e.g., 5,000-fold for IFNγ and 250-fold for MCP-1. Bystander activation of T and B cells was registered by an increased number of cells double positive for CD69/TCRβ and B7.2/CD19, respectively (Fig. 3 b). This early burst of cytokines might explain the increased expression of VCAM-1, which can be induced by proinflammatory cytokines, and I-Ab, which is induced by IFNγ. The increased levels of circulating MCP-1 might be significant for the exacerbated lesion development in αGalCer-treated mice, since this chemokine has important proatherogenic effects (21, 22). High levels of IL-6 could also have effects on atherosclerosis, since early lesions in apoE−/− mice are exacerbated by recombinant IL-6 (23). Elevated circulating IL-6 concentrations is correlated with increased risk of coronary and peripheral atherosclerosis in man (24). After repeated injections, serum levels of cytokines fell below the detection limit, and no signs of increased T or B cell activation could be detected anymore. Real-time RT-PCR analysis (see Supplemental Materials and Methods, available at http://www.jem.org/cgi/content/full/jem.20030997/DC1) of spleen mRNA confirmed the increase in IFNγ (85-fold) and IL-4 (25-fold) mRNA in mice injected once with αGalCer (Fig. 3 c) and demonstrated that increased IFNγ and IL-4 expression in the spleen was still detectable after repeated injections (Fig. 3 c).

Bottom Line: Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response.Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta.Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

ABSTRACT
Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E-deficient (apoE-/-) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE-/- mice crossed with CD1d-/- (CD1d-/-apoE-/-) mice exhibited a 25% decrease in lesion size compared with apoE-/- mice. Administration of alpha-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE-/- mice, whereas it did not affect lesion size in apoE-/-CD1d-/- mice. Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.

Show MeSH
Related in: MedlinePlus