title: Increased sensitivity of Apolipoprotein E knockout mice to swainsonine dependent immunomodulation.
abstract: The mechanisms that mediate accelerated atherosclerosis in autoimmune diseases remain unclear. One common mechanism that has been documented in autoimmune diseases and atherosclerosis is formation of hypoglycosyalted N-glycans on the cell surface. In this study we tested the effects of swainsonine, a class II α-mannosidase inhibitor which results in formation of hypoglycosylated N-glycans, on atherogenesis and immune cell dynamics in the atheroprone and hypercholesterolemic ApoE -/- mouse. Wild type or ApoE-/- mice (8 weeks of age) were fed a normal chow diet and administered swainsonine via the drinking water for 8 weeks at which time, atherosclerosis, and systemic markers of markers of inflammation were evaluated. Interestingly, no change in the rate of atherosclerosis development was observed in ApoE -/- mice treated with swainsonine. However, swainsonine significantly increased the number of peripheral blood leukocytes in ApoE -/- mice, with trends toward similar increases in swainsonine treated wild type mice noted. Assessment of leukocyte subsets using specific markers of all major blood lineages indicated that the increase in circulating leukocytes was due to the elevated number of progenitor cells. Consistent with swainsonine having a greater effect in ApoE -/- vs. wild type mice, increases in circulating inflammatory markers (IgA, IgG and chemokines) were observed in the former. Collectively, these data demonstrate that predisposition of ApoE -/- mice to vascular disease is associated with sensitization to the immunomodulatory effects of swainsonine and indicate that changes in N-glycans may provide a mechanism linking autoimmunity to atherogenesis.
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Leland L
authors.initials: LL
authors.lastname: Black
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Vallejo
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: janusz@uab.edu.
authors.forename: Janusz H
authors.initials: JH
authors.lastname: Kabarowski
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: rakeshp@uab.edu.
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000276:immunology; D005434:Flow Cytometry; D006031:Glycosylation; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011134:Polysaccharides / Q000276:immunology / Q000378:metabolism; D017026:Swainsonine / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D018941:Antigens, CD19; D001057:Apolipoproteins E; D039481:CD11b Antigen; D015704:CD4 Antigens; D016827:CD8 Antigens; D018925:Chemokines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011134:Polysaccharides; D017026:Swainsonine
keywords: Atherosclerosis; Hypoglycosylation; Inflammation; Leukocytes; N-glycan