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