Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Stergioti Eirini-Maria
Dissertation committee:
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Μπερτσιάς, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Παναγιώτης Βεργίνης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Δημήτριος Βασιλόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Ρουμπελάκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Θέμις Αλισσάφη, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αντώνης Φανουριάκης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Non-classical monocytes in systemic lupus erythematosus (SLE): Molecular and functional characterization
Translated title:
Non-classical monocytes in systemic lupus erythematosus (SLE): Molecular and functional characterization
Summary:
Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease that manifests diverse clinical and molecular abnormalities attributed to the loss of self-tolerance to nucleic acids and endogenous antigens and sustained autoantibody production. Excessive and irreversible tissue damage caused by autoantibodies and immune-complex deposition affects multiple organs leading to significant morbidity and increased mortality. Peripheral blood monocytes propagate inflammation and the development of end-organ damage in SLE. Three major populations of monocytes have been recognized namely classical (CM), intermediate (IM) and non-classical monocytes (NCM). Aberrations in monocytic pathophysiology underlie the SLE pathology and lead to perpetuation of inflammation and tissue injury. Recent studies emphasize the involvement of terminally differentiated immune cell subsets on tissue damage and severity of the disease. Despite the compelling evidence that NCM substantially contribute to disease progression in the target tissues, they remain the least explored subtype. The aim of this study is to further investigate the role and function of NCM in SLE. Understanding the molecular pathways involved in NCM activation and function in the periphery of patients with active SLE, before migrating into the tissues can guide the development of targeted therapies to modulate their effects. To this end, we performed a comprehensive transcriptomic, proteomic and functional characterization of the three peripheral monocytic subsets from active SLE patients and healthy individuals. Our data demonstrate extensive molecular disruptions in circulating SLE NCM, characterized by enhanced inflammatory features such as deregulated DNA repair and cell cycle and heightened IFN signaling combined with differentiation and developmental cues. Enhanced DNA damage, elevated expression of p53, G0 arrest of cell cycle and increased autophagy stress the differentiation potential of NCM in SLE. This immunogenic profile is associated with an activated macrophage phenotype of NCM exhibiting M1 features in the circulation, fueling the inflammatory response. Together, these findings identify circulating SLE NCM as a pathogenic cell type in the disease that could represent an additional therapeutic target.
Main subject category:
Health Sciences
Keywords:
Systemic lupus erythematosus, Non-classical monocytes, M1 macrophages, Differentiation, Transcriptomic/Proteomic analysis
Number of references:
204
