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Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

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Serum E-selectin specific antibodies.Serum was collected after 7 weeks on a high-fat diet. (A) Human E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group). (B) Mouse E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group).
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pone-0020620-g005: Serum E-selectin specific antibodies.Serum was collected after 7 weeks on a high-fat diet. (A) Human E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group). (B) Mouse E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group).

Mentions: In both of the A and B regimens, serum human E-selectin-specific IgG1 and total IgG were detected in E-selectin tolerized mice (Figure 5A), whereas IgG2a levels were similarly low in both groups. The elevated serum IgG1 was proportional to elevated serum total IgG. Serum mouse E-selectin-specific IgG1 and total IgG were increased in E-selectin tolerized mice and the elevated serum IgG1 was proportional to elevated serum total IgG (Figure 5B), demonstrating cross-reactivity of human E-selectin specific antibodies to mouse E-selectin. Serum E-selectin- specific IgM was analyzed in regimen A; available serum was insufficient for this analysis in regimen B. E-selectin specific IgM did not differ between treatment groups, which is consistent with our studies in C57BL/6 mice with and without EAE (data not shown). Background antibody binding was negligible when OVA was used to coat the ELISA plates. The absorbance of serum from PBS or E-selectin treated mice was as low as the no serum control; whereas the serum levels of OVA-specific IgG and IgG1 were high in OVA immunized mice (data not shown).


Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Serum E-selectin specific antibodies.Serum was collected after 7 weeks on a high-fat diet. (A) Human E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group). (B) Mouse E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119064&req=5

pone-0020620-g005: Serum E-selectin specific antibodies.Serum was collected after 7 weeks on a high-fat diet. (A) Human E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group). (B) Mouse E-selectin specific IgG1, IgG2a and total IgG in mice on regimen A (N = 5 per group) or regimen B (N = 24 for PBS group, N = 23 for E-selectin group).
Mentions: In both of the A and B regimens, serum human E-selectin-specific IgG1 and total IgG were detected in E-selectin tolerized mice (Figure 5A), whereas IgG2a levels were similarly low in both groups. The elevated serum IgG1 was proportional to elevated serum total IgG. Serum mouse E-selectin-specific IgG1 and total IgG were increased in E-selectin tolerized mice and the elevated serum IgG1 was proportional to elevated serum total IgG (Figure 5B), demonstrating cross-reactivity of human E-selectin specific antibodies to mouse E-selectin. Serum E-selectin- specific IgM was analyzed in regimen A; available serum was insufficient for this analysis in regimen B. E-selectin specific IgM did not differ between treatment groups, which is consistent with our studies in C57BL/6 mice with and without EAE (data not shown). Background antibody binding was negligible when OVA was used to coat the ELISA plates. The absorbance of serum from PBS or E-selectin treated mice was as low as the no serum control; whereas the serum levels of OVA-specific IgG and IgG1 were high in OVA immunized mice (data not shown).

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

Show MeSH
Related in: MedlinePlus