Type I IFN signature in childhood-onset systemic lupus erythematosus: A conspiracy of DNA- and RNA-sensing receptors?
Background: Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients. Methods: The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs). Innate immune receptor expression was determined by RT-PCR and flow cytometry. To clarify the contribution of RNA-binding RIG-like receptors (RLRs) and DNA-binding receptors (DBRs) to IFN-I activation, peripheral blood mononuclear cells (PBMCs) from patients were treated with BX795, a TANK-binding kinase 1 (TBK1) inhibitor blocking RLR and DBR pathways. Results: The IFN-I signature was positive in 57% of cSLE patients and 15% of the HCs. Upregulated gene expression of TLR7, RLRs (IFIH1, DDX58, DDX60, DHX58) and DBRs (ZBP-1, IFI16) was observed in CD14+ monocytes of the IFN-I-positive cSLE patients. Additionally, RIG-I and ZBP-1 protein expression was upregulated in these cells. Spontaneous IFN-I stimulated gene (ISG) expression in PBMCs from cSLE patients was inhibited by a TBK1-blocker. Conclusions: IFN-I activation, assessed as ISG expression, in cSLE is associated with increased expression of TLR7, and RNA and DNA binding receptors, and these receptors contribute to IFN-I activation via TBK1 signaling. TBK1-blockers may therefore be a promising treatment target for SLE.
|Keywords||Childhood-onset SLE, Cytosolic nucleic receptors, Interferon type I, TBK1, TLR7|
|Persistent URL||dx.doi.org/10.1186/s13075-017-1501-z, hdl.handle.net/1765/104061|
|Journal||Arthritis Research & Therapy|
Wahadat, M.J. (M. Javad), Bodewes, I.L.A. (Iris L.A.), de Maria, M, van Helden-Meeuwsen, C.G, van Dijk-Hummelman, A, Steenwijk, E.C. (Eline C.), … Versnel, M.A. (2018). Type I IFN signature in childhood-onset systemic lupus erythematosus: A conspiracy of DNA- and RNA-sensing receptors?. Arthritis Research & Therapy, 20(1). doi:10.1186/s13075-017-1501-z