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Identifier 000403586
Title Characterizing IL-33/ST2L axis contribution to SLE pathogenesis
Alternative Title Ρόλος του σηματοδοτικού μονοπατιού IL-33/ST2L στους μηχανισμούς παθογένειας του ΣΕΛ
Author Γεωργάκης, Σπύρος Α.
Thesis advisor Μπερτσιάς, Γεώργιος
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease of aberrant DNA sensing and prominent IFN-a signature in peripheral blood immune cells that culminates in the production of pathogenic anti-dsDNA autoantibodies and extensive organ injury. Neutrophil extracellular traps (NETs) are characterized as major sources of DNA-related autoantigens and their impaired clearance is correlated to disease exacerbation. Several alarmins are attached to DNA filaments and enhance their interferogenic capacity. IL-33, a newly characterized alarmin, is a major regulator of innate defense but its contribution on NETotic procedure hasn’t been delineated yet. Soluble ST2, the decoy receptor of IL-33, is elevated in SLE patients unravelling a possible role of our alarmin of interest in SLE progression. The goal of this thesis is to define IL-33s role on NETosis and its effect on the interferogenic capacity of NETs. Conclusively, we want to reveal the role of IL-33/ST2L axis on SLE progression. Surprisingly, recombinant IL-33 promoted NET formation. PMA-mediated NETs from healthy neutrophils were IL-33 decorated and SLE ΝΕΤs tend to have enhanced IL33-NET decoration compared with healthy neutrophils. IL-33 decoration of NETs promoted their interferogenic capacity when added in pDC culture that hypoexpressed ST2L (IL-33R). Additionally, TLR9 signaling seem to regulate ST2L surface expression. To conclude, IL-33 promotes NET formation. IL-33 decoration of NETs enhances their interferogenic capacity and because of their impaired clearance elevated bioavailability of IFN-a is monitored. IFN-a primes neutrophils to form more NET structures providing a positive feedback loop which leads to SLE exacerbation. Better understanding of the mode of action, regulation and function of IL-33 would further facilitate the development of therapeutics that modulate IL-33–ST2 signaling to treat SLE and other autoimmune, or not, diseases.
Language English
Subject IFN-a
PMNs
Systemic Lupus Erythematosus
Πολυμορφοπύρηνα
Συστηματικός Ερυθηματώδης Λύκος
Issue date 2016-11-18
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
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