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Identifier 000443959
Title Interleukin-33 and its contribution on innate immune mechanisms that mediate autoimmune manifestations of Systemic Lupus Erythematosus (SLE)
Alternative Title Ο ρόλος της ιντερλευκίνης-33 στους μηχανισμούς φυσικής ανοσίας που επάγουν την αυτοανοσία στον Συστηματικό Ερυθηματώδη Λύκο (ΣΕΛ)
Author Γεωργάκης, Σπύρος
Thesis advisor Μπερτσιάς, Γεώργιος
Reviewer Σιδηρόπουλος, Πρόδρομος
Δράκος, Ηλίας
Abstract Systemic Lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by aberrant immune activation, defective clearance mechanisms, autoantibody formation, immune complexes accumulation and a profound type I IFN gene signature. One of the primary sources of IFNα are plasmacytoid dendritic cells (pDCs) especially in response to Toll-like receptor(TLR)-7/9- and nucleic acid cytoplasmic sensors-mediated signaling. Additionally, transcriptomic and functional assays indicated that SLE neutrophils exhibit an over-activated status and enhanced capacity to form chromatin extracellular traps (NETs) which are considered key players in SLE pathogenesis. Pathogenic vicious feedback loops taking place in SLE can subsequently lead to end organ damage. Interleukin-33 (IL-33), a nuclear alarmin released mainly during necrotic cell death, exerts contextspecific effects on adaptive and innate immune cells eliciting potent inflammatory or anti-inflammatory responses. The soluble regulatory receptor of IL-33, sST2, was monitored to display up-regulated levels in SLE patients’ sera and was correlated to disease severity and renal involvement. IL-33 is mainly expressed by non-hematopoietic cells of barrier tissues while recent findings suggest it is also released by immune cells upon inflammatory or damage/death-related stimuli. Until now, the role of neutrophilderived IL-33 in autoimmunity has not been investigated. The main research questions addressed in this study are a) if SLE neutrophils exhibit differential expression levels of IL-33, b) If SLE-relevant stimuli promote the release of IL-33 decorated NETs, c) if SLE NETs display their inflammatory effects in an IL-33-dependent manner and, d) if IL-33 decorated NETs exhibit in vivo significance regarding SLE pathogenesis. Herein, we demonstrated that SLE neutrophils exhibit relatively increased IL-33 mRNA levels and the ability to release IL-33 decorated NETs both spontaneously and after IC-stimulation. IC-mediated NETs enhance IFN-α response by pDCs in a IL33R- (ST2L-) and IRF-7-dependent manner. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Notably, a focused proteomic analysis (PRM) and ex vivo functional aasays 7 revealed that SLE patient-derived NETs are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFN-α production elicited by NETs. Regarding their in vivo significance in SLE, IL-33 decorated NETs were found up-regulated in SLE patients’ peripheral blood and were also detected at relevant inflamed tissues (kidneys, skin). To conclude, by using a combination of molecular, imaging and proteomic approaches, we revealed that SLE neutrophils -activated by disease immunocomplexes- release bioactive IL-33-bearing NETs exhibiting potent interferogenic capacity. These data support a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, IFN-α production and end-organ inflammation.
Language English
Subject Alarmins
Neutrophil extracellular (NETs)
Plasmacytoid dendritic cells (pDCs)
Issue date 2021-12-01
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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