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Identifier 000460274
Title Regulation of monocyte intracellular metabolism in the inflammatory environment of systemic lupus erythematosus (SLE)
Alternative Title Ρύθμιση του ενδοκυττάριου μεταβολισμού των μονοκύτταρων στο φλεγμονώδες περιβάλλον του συστηματικού ερυθηματώδη λύκου
Author Παμπούκα, Κωνσταντίνα
Thesis advisor Μπερτσιάς, Γεώργιος
Reviewer Σεμιτεκόλου, Μαρία
Νικολέρη, Δήμητρα
Abstract Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by dysregulated immune responses, chronic inflammation, and organ damage [1]. In SLE, type I interferon (IFN) instructs monocytes to become activated and produce inflammatory mediators. Seminal studies in the metabolome of SLE patient-derived sera have revealed distinct perturbations of lipid metabolism and oxidative phosphorylation [2]–[4]. Additionally, in macrophages, IFNα signaling is implicated in cholesterol reprogramming in the context of viral infections, thus facilitating specific effector functions and intensify inflammatory phenotypes [5]. To this end, the metabolic alterations of SLE monocytes under the effect of type I IFN, as well as their contribution to disease pathogenesis remain ill-defined. Our objective it to delineate the metabolic repercussions of monocytes in response to prolonged IFNα signaling in the context of SLE disease. Using RNA sequencing, we identified significant enrichment of inflammation and lipid-related genes, implicated in cholesterol homeostasis, in healthy monocytes treated with recombinant IFNα. These IFNα-stimulated monocytes exhibited a significant overlap in differentially expressed genes (DEGs) with SLE CD14+ monocytes with robust IFN gene signature (IFNααhigh SLE monocytes) as compared to those with an IFNααlow gene signature. The direct effects of IFNα on cholesterol synthesis pathways were confirmed by demonstrating increased intracellular cholesterol levels and enhanced lipid droplet formation both in IFNα-stimulated and SLE patient-derived monocytes. Notably, blockade of cholesterol biosynthesis was able to reverse the IFNα-mediated inflammatory phenotype of monocytes including the secretion of IL-6 and TNF-αα. In conclusion, our preliminary data suggest that IFNα-mediated perturbations in lipid-related pathways may contribute to the development of SLE inflammation, offering a mechanistic explanation for the increased disease burden among IFNααhigh SLE patients.
Language English
Subject Cholesterol
Immunometabolism
Ανοσομεταβολισμός
Λύκος
Μονοκύτταρα
Χοληστερόλη
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/d/b/8/metadata-dlib-1699606419-186528-9964.tkl Bookmark and Share
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