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Identifier 000460391
Title The role of hypercholesterolemia in the pathogenesis of rheumatoid arthritis and the immune cell metabolism
Alternative Title ο ρόλος της υπερχοληστερολαιμίας στην παθογέννεση της ρευματοειδούς αρθρίτιδας και τον μεταβολισμό των ανοσοκυττάρων
Author Κακαλέ, Ασημίνα
Thesis advisor Καρδάσης, Δημήτριος
Abstract Hypercholesterolemia associated with atherosclerotic disease leads to systemic effects including compromised immunity. In line, increased total cholesterol levels constitute a risk factor for Rheumatoid Arthritis (RA). The specific mechanisms that link excess cholesterol accumulation with RA still remain elusive. In this study, we used Apolipoprotein E deficient (ApoE KO) mice, characterized by very high total cholesterol levels, to examine the role of cholesterol in autoimmunity. Characterization of the hypercholesterolemic mouse model revealed alongside with increased plasma total cholesterol, decreased high-density cholesterol (HDL-C) levels and altered HDL protective, anti-inflammatory properties. Cholesterol accumulation affected the immune phenotyping of T cells and macrophages in secondary lymphoid organs, and especially the populations of CD8+ T cells, that decreased and the CD163+ macrophages that increased. ApoE KO mice exhibited increased severity of Ag-induced arthritis (AIA) compared with wild-type mice, and this was associated with elevated CD4+/CD8+ ratio and the CD4+CD25+ Tregs in both spleen and draining lymph nodes, as well as with increased expression levels of pro-inflammatory markers, including CD86, CD80, CD36 and MHC-II in spleen macrophages. Inhibition of cholesterol biosynthesis with a lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMG-CoAR) inhibitor, simvastatin, attenuated AIA, but resulted in the development of toxic side effects. Decreased daily dose of simvastatin reduced the plasma total cholesterol levels and increased even more the CD4+CD25+ Treg population. Interestingly, an increase in the expression of the hypoxia-inducible factor 1 (Hif1a) associated with inflammation in lymph nodes was observed. These findings reveal that ApoE deficiency and subsequent accumulation of cholesterol in the plasma exacerbated inflammatory arthritis possibly via changes on HDL functionality and immune cell activation.
Language English
Subject Ανοσοκύτταρα
Ρευματοειδής αρθρίτιδα
Issue date 2023-12-08
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/a/1/c/metadata-dlib-1700563969-754519-20665.tkl Bookmark and Share
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