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. 2012 Jan;220(1):110-7.
doi: 10.1016/j.atherosclerosis.2011.10.012. Epub 2011 Oct 17.

P-selectin glycoprotein ligand-1 deficiency leads to cytokine resistance and protection against atherosclerosis in apolipoprotein E deficient mice

Wei Luo  1 , Hui Wang, Miina K Ohman, Chiao Guo, Kate Shi, Julia Wang, Daniel T Eitzman
Affiliations

P-selectin glycoprotein ligand-1 deficiency leads to cytokine resistance and protection against atherosclerosis in apolipoprotein E deficient mice

Wei Luo et al. Atherosclerosis. 2012 Jan.

Abstract

Adhesive interactions between endothelial cells and leukocytes contribute to atherosclerotic plaque growth. However, mechanism(s) responsible for endothelial priming and deactivation in inflammatory diseases such as atherosclerosis are not clear. Apolipoprotein E deficient mice were generated with deficiency of P-selectin glycoprotein ligand-1 (Psgl-1(-/-), ApoE(-/-)). On both standard chow and Western diet, Psgl-1(-/-), ApoE(-/-) mice were protected against atherosclerosis compared to Psgl-1(+/+), ApoE(-/-) controls. Psgl-1(-/-), ApoE(-/-) mice also showed reduced leukocyte rolling and firm attachment on endothelial cells, however, adoptively transferred Psgl-1(+/+), ApoE(-/-) leukocytes into Psgl-1(-/-), ApoE(-/-) hosts displayed similar reduced rolling as Psgl-1(-/-), ApoE(-/-) leukocytes. Hematopoietic deficiency of Psgl-1 conferred resistance to the effects of interleukin-1β (IL-1β) on leukocyte rolling along with reduced circulating levels of sP-sel and sE-sel. Antibody blockade of Psgl-1 also reduced endothelial activation in response to IL-1β, eliminated leukocyte rolling, and was protective against atherosclerosis in ApoE(-/-) mice. Monocyte depletion with clodronate restored the endothelial response to IL-1β in Psgl-1(-/-) mice. This study suggests that Psgl-1 deficiency leads to reduced atherosclerosis and adhesive interactions between endothelial cells and leukocytes by indirectly regulating endothelial responses to cytokine stimulation.

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Figures

Figure 1
Figure 1. Effect of Psgl-1 status on leukocyte-endothelial (L-E) interactions
A) L-E interactions in Psgl-1+/+, ApoE−/− mice that received either Psgl-1+/+, ApoE−/− (white bar) or Psgl-1−/−, ApoE−/− bone marrow transplants (black bar) at baseline and B) 6 hours post IL-1β challenge. C) Adoptively transferred leukocytes from Psgl-1+/+, ApoE−/− donors into Psgl-1+/+, ApoE−/− (white bar) or Psgl-1−/−, ApoE−/− recipients (black bar). D) Psgl-1+/+, ApoE−/− mice with control antibody (white bar) or 4RA10 (black bar). Representative intravital microscopy image of venule from Psgl-1+/+, ApoE−/− mouse treated with E) control antibody or with F) 4RA10. Arrows point to rhodamine labeled leukocytes. *P<0.05. **P<0.001. ***P<0.0001. N= 5 per group.
Figure 2
Figure 2. Effect of Psgl-1 status on circulating levels of sP-sel and sE-sel
A) sP-sel and B) sE-sel levels from 13 week old mice on Western diet for 9 weeks, and 30 week old mice maintained on standard diet; Psgl-1+/+, ApoE−/− (white bar) and Psgl-1−/−, ApoE−/− (black bar). C) sP-sel and D) sE-sel levels in Psgl-1+/+, ApoE−/− mice after either Psgl-1+/+, ApoE−/− (white bar) or Psgl-1−/−, ApoE−/− bone marrow transplantation (black bar). E) sP-sel and F) sE-sel levels in Psgl-1+/+, ApoE−/− mice treated with control antibody (white bar) or 4RA10 (black bar). *P<0.05. **P<0.001. ***P<0.0001. N=9 per genotype.
Figure 3
Figure 3. Effect of Psgl-1 antibody blockade given after IL-1β on sP-sel levels
Circulating levels of sP-sel in Psgl-1+/+, ApoE−/− mice in which IV control antibody (dashed line) or 4RA10 (solid line) was administered (arrow) 2.5 hours after IL-1β stimulation at a time point when sP-sel levels were rising in plasma. *P<0.02. N=4 per genotype.
Figure 4
Figure 4. Effect of monocyte depletion on sP-sel levels in Psgl-1+/+, ApoE−/− and Psgl-1−/−, ApoE−/− mice
Circulating levels of sP-sel in Psgl-1+/+, ApoE−/− and Psgl-1−/−, ApoE−/− mice treated with PBS or clodronate liposome before (white bar) and after IL-1β (black bar). *P<0.05. **P<0.001. N=3 per genotype.
Figure 5
Figure 5. Effect of Psgl-1 deficiency on atherosclerosis
Representative en face view of aortic trees stained with oil-red-O from A) Psgl-1+/+, ApoE−/− and B) Psgl-1−/−, ApoE−/− 13 week old mice on Western diet for 9 weeks; and C) Psgl-1+/+, ApoE−/− and D) Psgl-1−/−, ApoE−/− 30 week old mice on standard chow. E) Mean % surface area of aortic arch covered with lipid-rich atherosclerotic lesions. *P<0.05. **P<0.001. N=11–15 per genotype.
Figure 6
Figure 6. Effect of Psgl-1 antibody blockade with 4RA10 on atherosclerosis
Representative en face view of aortic trees stained with oil-red-O from mice treated with 9 weekly injections of A) Control IgG k antibody or B) 4RA10. C) Mean % surface area of aortic arch covered with lipid-rich atherosclerotic lesions. *P<0.03. N=8 per genotype.
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