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08.31 Unravelling the role of il33/st2l axis on sustained ifn-a production in systemic lupus erythematosus
  1. Spiridon Georgakis1,2,
  2. Garyfallia Papadaki1,2,
  3. Irene Gergianaki4,
  4. Prodromos Sidiropoulos1,2,4,
  5. Panagiotis Verginis3,
  6. Aikaterini Gkirtzimanaki1,2,*,
  7. George Bertsias1,2,4,*
  1. 1Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
  2. 2Laboratory of Rheumatology, Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece
  3. 3Biomedical Research Foundation, Academy of Athens, Athens, Greece
  4. 4Department of Rheumatology, University of Crete Medical School, Heraklion, Crete, Greece
  5. *equal contribution

Abstract

Background In Systemic Lupus Erythematosous (SLE), extracellular DNA (as in extracellular chromatin traps or immune complexes) combined with alarmins/danger- associated molecular patterns promote the production of IFNa by plasmatocytoid dendritic cells (pDCs).123 IL-33 is a cell necrosis-derived alarmin with immunostimulatory properties which depend on the context of immune cells and inflammatory milieu.4 We hypothesised that IL-33 might augment the interferogenic potential of extracellular DNA in SLE.

Materials and methods Human peripheral blood pDCs were isolated from SLE patients and healthy individuals and IL-33 receptor (ST2L) expression was determined by flow cytometry and RT-PCR. Oligonucleotides (CpG ODNs) were administered with/without recombinant IL-33 and IFN-a production was measured by RT-PCR and ELISA. IL-33 decoration of neutrophil extracellular traps (NETs) was examined using immunofluorescence and confocal microscopy. pDCs were stimulated with NETs-containing supernatants with/without recombinant IL-33 and IFN-a production was measured.

Results Spontaneous-released NETs from peripheral blood neutrophils of active SLE patients were decorated with IL-33 to larger extent compared to healthy-derived NETs. Circulating CD303+/CD123+ pDCs from active SLE patients exhibited membrane expression of ST2L albeit at lower levels compared to healthy pDCs (p<0,05). Combined CpG/IL-33 activation of pDCs promoted enhanced IFN-a mRNa and protein levels compared to CpG alone (p<0,05). Moreover, co-administration of IL-33 and NET-containing supernatants on pDCs significantly enhanced IFN-a protein and mRNA levels (p<0,05).

Conclusions The alarmin IL-33 produced by SLE NETing neutrophils promotes IFN-a production by pDCs therefore contributing to autoimmune inflammatory responses.

Topic Autoimmune inflammation

References

  1. Garcia-Romo, G. S., S. Caielli, B. Vega, et al. ”Netting Neutrophils Are Major Inducers of Type I IFN Production in Paediatric Systemic Lupus Erythematosus.”Science Translational Medicine 2011;3:73.

  2. Lande R., Gregorio J., Facchineti V., et al. ‘’Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.’’Nature2007;449.

  3. Tian, Jane, Ana Maria Avalos, Su-Yau Mao, et al. ”Toll-like Receptor 9–dependent Activation by DNA-containing Immune Complexes Is Mediated by HMGB1 and RAGE.”Nature Immunology 2007;8.5:487–96

  4. Duan, Lihua, Jie Chen, Feili Gong, et al. “The Role of IL-33 in Rheumatic Diseases.” Clinical and Developmental Immunology2013:1–5.

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