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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 the expression of VCAM-1 and I-Ab in atherosclerotic lesions. Experimental groups were the same as in Fig. 1. (a) VCAM-1 quantitation (VCAM-1+ area/vessel area); (b and c) representative sections of aortic root stained for VCAM-1 by avidin-biotin-immunoperoxidase (brown) (×50 and ×400). (d) I-Ab quantitation (I-Ab+ cells/total hematoxylin+ cells) and (e) representative sections of aortic roots stained for I-Ab by avidin-biotin-immunoperoxidase (brown) (×400). Arrows point at I-Ab+ cells. Mean ± SEM (*P < 0.05 versus apoE−/− treated with PBS and versus all apoE−/−CD1d−/−; **P < 0.01 versus all apoE−/−CD1d−/− mice; §P < 0.05 versus apoE−/−-PBS).
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fig2: Effects of CD1d deficiency and αGalCer treatment on the expression of VCAM-1 and I-Ab in atherosclerotic lesions. Experimental groups were the same as in Fig. 1. (a) VCAM-1 quantitation (VCAM-1+ area/vessel area); (b and c) representative sections of aortic root stained for VCAM-1 by avidin-biotin-immunoperoxidase (brown) (×50 and ×400). (d) I-Ab quantitation (I-Ab+ cells/total hematoxylin+ cells) and (e) representative sections of aortic roots stained for I-Ab by avidin-biotin-immunoperoxidase (brown) (×400). Arrows point at I-Ab+ cells. Mean ± SEM (*P < 0.05 versus apoE−/− treated with PBS and versus all apoE−/−CD1d−/−; **P < 0.01 versus all apoE−/−CD1d−/− mice; §P < 0.05 versus apoE−/−-PBS).

Mentions: To assess inflammatory activation, lesions in the aortic root were stained for the adhesion molecule VCAM-1 and the MHC class II protein I-Ab. VCAM-1 was expressed in the lesion and in the media underneath the lesion (Fig. 2, a–c). αSM-actin staining of adjacent aortic root sections confirmed that VCAM-1 was mainly expressed by smooth muscle cells (not depicted). I-Ab was expressed by inflammatory cells in the lesions (Fig. 2, d and e). ApoE−/− CD1d−/− mice expressed significantly less VCAM-1 than apoE−/− mice (P = 0.027) (Fig. 2 a). The proportion of I-Ab–expressing cells did not differ between apoE−/− and apoE−/−CD1d−/− mice (Fig. 2 d); however, the decrease in lesion area in the CD1d−/− mice resulted in a reduced number of I-Ab cells per section when compared with apoE−/− mice. αGalCer treatment increased VCAM-1 and I-Ab expression in apoE−/− mice (P = 0.036) but not in apoE−/− CD1d−/− mice (Fig. 2, a–e), implying that αGalCer induction of these genes was dependent on CD1d-restricted NKT cells.


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 the expression of VCAM-1 and I-Ab in atherosclerotic lesions. Experimental groups were the same as in Fig. 1. (a) VCAM-1 quantitation (VCAM-1+ area/vessel area); (b and c) representative sections of aortic root stained for VCAM-1 by avidin-biotin-immunoperoxidase (brown) (×50 and ×400). (d) I-Ab quantitation (I-Ab+ cells/total hematoxylin+ cells) and (e) representative sections of aortic roots stained for I-Ab by avidin-biotin-immunoperoxidase (brown) (×400). Arrows point at I-Ab+ cells. Mean ± SEM (*P < 0.05 versus apoE−/− treated with PBS and versus all apoE−/−CD1d−/−; **P < 0.01 versus all apoE−/−CD1d−/− mice; §P < 0.05 versus apoE−/−-PBS).
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fig2: Effects of CD1d deficiency and αGalCer treatment on the expression of VCAM-1 and I-Ab in atherosclerotic lesions. Experimental groups were the same as in Fig. 1. (a) VCAM-1 quantitation (VCAM-1+ area/vessel area); (b and c) representative sections of aortic root stained for VCAM-1 by avidin-biotin-immunoperoxidase (brown) (×50 and ×400). (d) I-Ab quantitation (I-Ab+ cells/total hematoxylin+ cells) and (e) representative sections of aortic roots stained for I-Ab by avidin-biotin-immunoperoxidase (brown) (×400). Arrows point at I-Ab+ cells. Mean ± SEM (*P < 0.05 versus apoE−/− treated with PBS and versus all apoE−/−CD1d−/−; **P < 0.01 versus all apoE−/−CD1d−/− mice; §P < 0.05 versus apoE−/−-PBS).
Mentions: To assess inflammatory activation, lesions in the aortic root were stained for the adhesion molecule VCAM-1 and the MHC class II protein I-Ab. VCAM-1 was expressed in the lesion and in the media underneath the lesion (Fig. 2, a–c). αSM-actin staining of adjacent aortic root sections confirmed that VCAM-1 was mainly expressed by smooth muscle cells (not depicted). I-Ab was expressed by inflammatory cells in the lesions (Fig. 2, d and e). ApoE−/− CD1d−/− mice expressed significantly less VCAM-1 than apoE−/− mice (P = 0.027) (Fig. 2 a). The proportion of I-Ab–expressing cells did not differ between apoE−/− and apoE−/−CD1d−/− mice (Fig. 2 d); however, the decrease in lesion area in the CD1d−/− mice resulted in a reduced number of I-Ab cells per section when compared with apoE−/− mice. αGalCer treatment increased VCAM-1 and I-Ab expression in apoE−/− mice (P = 0.036) but not in apoE−/− CD1d−/− mice (Fig. 2, a–e), implying that αGalCer induction of these genes was dependent on CD1d-restricted NKT cells.

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