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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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Effects of CD1d deficiency and αGalCer treatment on atherosclerosis. 5-wk-old female apoE−/− and apoE−/−CD1d−/− mice were injected twice a week for 10 wk with αGalCer or PBS and killed 48 h after the last injection (n = 12 for each group). (a) Mean lesion size in Oil Red O–stained aortic root sections. Mean ± SEM (***P < 0.001 versus apoE−/−-PBS and all apoE−/−CD1d−/−; §§P < 0.01 versus apoE−/−-PBS mice). (b) Lesion size at every 100 μm for the first 600 μm of the aortic root in apoE−/− and apoE−/−CD1d−/− mice. (c) Representative Oil Red O–stained cryosections of aortic roots (magnification ×50).
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fig1: Effects of CD1d deficiency and αGalCer treatment on atherosclerosis. 5-wk-old female apoE−/− and apoE−/−CD1d−/− mice were injected twice a week for 10 wk with αGalCer or PBS and killed 48 h after the last injection (n = 12 for each group). (a) Mean lesion size in Oil Red O–stained aortic root sections. Mean ± SEM (***P < 0.001 versus apoE−/−-PBS and all apoE−/−CD1d−/−; §§P < 0.01 versus apoE−/−-PBS mice). (b) Lesion size at every 100 μm for the first 600 μm of the aortic root in apoE−/− and apoE−/−CD1d−/− mice. (c) Representative Oil Red O–stained cryosections of aortic roots (magnification ×50).

Mentions: ApoE−/−CD1d−/− mice exhibited significantly smaller atherosclerotic lesions in the aortic root than apoE−/− single knockout mice (74,638 ± 5.9 μm2 versus 100,548 ± 5.6 μm2; P = 0.0087) (Fig. 1, a–c). This was apparent throughout the aortic root (Fig. 1 b). When CD1d-restricted NKT cells were activated by administration of αGalCer over a 10-wk period, lesion size increased by 50% in apoE−/− mice compared with PBS-treated control mice (151,276 ± 9.377 μm2 versus 100,548 ± 5.572 μm2; P < 0.0001). In apoE−/− CD1d−/− mice, αGalCer did not affect lesion size (Fig. 1, a and c), demonstrating that the effect of αGalCer on atherosclerosis depends on CD1d. Together, these findings indicate that CD1d-dependent activation of NKT cells aggravates atherosclerosis and that lack of CD1d, the restriction element for presentation of lipid antigens to NKT cells, leads to reduced lesions in a mouse model of human atherosclerosis.


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)

Effects of CD1d deficiency and αGalCer treatment on atherosclerosis. 5-wk-old female apoE−/− and apoE−/−CD1d−/− mice were injected twice a week for 10 wk with αGalCer or PBS and killed 48 h after the last injection (n = 12 for each group). (a) Mean lesion size in Oil Red O–stained aortic root sections. Mean ± SEM (***P < 0.001 versus apoE−/−-PBS and all apoE−/−CD1d−/−; §§P < 0.01 versus apoE−/−-PBS mice). (b) Lesion size at every 100 μm for the first 600 μm of the aortic root in apoE−/− and apoE−/−CD1d−/− mice. (c) Representative Oil Red O–stained cryosections of aortic roots (magnification ×50).
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Related In: Results  -  Collection

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fig1: Effects of CD1d deficiency and αGalCer treatment on atherosclerosis. 5-wk-old female apoE−/− and apoE−/−CD1d−/− mice were injected twice a week for 10 wk with αGalCer or PBS and killed 48 h after the last injection (n = 12 for each group). (a) Mean lesion size in Oil Red O–stained aortic root sections. Mean ± SEM (***P < 0.001 versus apoE−/−-PBS and all apoE−/−CD1d−/−; §§P < 0.01 versus apoE−/−-PBS mice). (b) Lesion size at every 100 μm for the first 600 μm of the aortic root in apoE−/− and apoE−/−CD1d−/− mice. (c) Representative Oil Red O–stained cryosections of aortic roots (magnification ×50).
Mentions: ApoE−/−CD1d−/− mice exhibited significantly smaller atherosclerotic lesions in the aortic root than apoE−/− single knockout mice (74,638 ± 5.9 μm2 versus 100,548 ± 5.6 μm2; P = 0.0087) (Fig. 1, a–c). This was apparent throughout the aortic root (Fig. 1 b). When CD1d-restricted NKT cells were activated by administration of αGalCer over a 10-wk period, lesion size increased by 50% in apoE−/− mice compared with PBS-treated control mice (151,276 ± 9.377 μm2 versus 100,548 ± 5.572 μm2; P < 0.0001). In apoE−/− CD1d−/− mice, αGalCer did not affect lesion size (Fig. 1, a and c), demonstrating that the effect of αGalCer on atherosclerosis depends on CD1d. Together, these findings indicate that CD1d-dependent activation of NKT cells aggravates atherosclerosis and that lack of CD1d, the restriction element for presentation of lipid antigens to NKT cells, leads to reduced lesions in a mouse model of human atherosclerosis.

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