FRI0268 Glucocorticoid-induced leucine zipper (GILZ) represents a checkpoint limiting type i interferon (IFN) production in sle
Authors: C.T. Nataraja, E.F. Morand, J. Thomas, J. Harris, S.A. Jones
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Glucocorticoids (GC) remain the mainstay of treatment in Systemic Lupus Erythematosus (SLE). Type I interferons (IFN), produced by plasmacytoid dendritic cells (pDC) in response to Toll-Like receptors (TLR) ligands, are critical to SLE pathogenesis, but are not suppressed by GC. Glucocorticoid-Induced Leucine Zipper (GILZ) is an endogenous anti-inflammatory protein induced by GC. Beaulieu et al., 2010 However, whether GILZ regulates IFN production in SLE is not known. <h3>Objectives</h3> To test the hypothesis that GILZ inhibits the production of Type I IFN in SLE. <h3>Methods</h3> We performed <i>in vitro</i> analysis on pDC and bone marrow-derived DC (BMDC), and <i>in vivo</i> studies, of WT and GILZ-/- mice using stimuli of TLR7 (Imiquimod), TLR7/8 (Resiquimod) and TLR9 (CpG). IFN was measured using a IFN luciferase assay, and other cytokines with ELISA. IFN-stimulated gene signatures (ISG) were measured using qPCR. To determine whether GILZ regulates IFN in human SLE, we mined a public gene expression dataset GSE10325. Becker et al., 2013 <h3>Results</h3> Deletion of GILZ resulted in excess pDC secretion of IFN in response to TLR7 (p=0.0012) and TLR9 (p=0.01) stimulation, and BMDC secretion of IFN, IL-6 and TNFα in response to TLR7 (p=0.0039, 0.017, 0.033), TLR7/8 (p=0.001,&lt;0.0001,&lt;0.0001) and TLR9 (p=0.005,&lt;0.0001, 0.0034) stimulation respectively. Dexamethasone (DEX) induced GILZ in WT pDC and BMDC, and TLR stimulation suppressed GILZ expression in BMDC, but TLR-stimulated GILZ-/- cell failed to suppress IFN in response to DEX. Moreover, GILZ deficiency was associated with increased ISG in naïve spleen cells, naïve BMDCs and TLR7/9 stimulated pDC of GILZ-/- mice compared to WT mice. Correspondingly, increased IFN was seen in GILZ-/- mice in response to TLR7/8 stimulation <i>in vivo</i>. In GSE10325<b>,</b> we show that lower expression of GILZ was associated with high ISG (<i>IFI44, IFI44L, RSAD2, IFI27)</i> (p=0.0021) in SLE patient peripheral blood B cells, and GILZ mRNA was negatively correlated with IFN signature (r=-0.63, p=0.017) which in turn positively correlated with disease activity (SLEDAI2k) (r=0.77, p=0.002). <h3>Conclusions</h3> GILZ is an endogenous regulator of increased IFN production in response to TLR stimulation <i>in vitro</i> and in mice, and is negatively correlated with ISG in human SLE. This suggests that GILZ negatively regulates type I IFN production and GILZ based therapy may be a potential therapeutic strategy that could reduce steroid dependence in SLE. <h3>References</h3> [1] Beaulieu E, Ngo D, Santos L, Yang YH, Smith M, Jorgensen C, … Morand EF. Glucocorticoid-induced leucine zipper is an endogenous antiinflammatory mediator in arthritis. Arthritis Rheum2010;62(9):2651–2661. doi:10.1002/art.27566 [2] Becker AM, Dao KH, Han BK, Kornu R, Lakhanpal S, Mobley AB, … Davis LS. SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One2013;8(6):e67003. doi:10.1371/journal.pone.0067003 <h3>Acknowledgements</h3> NHMRC <h3>Disclosure of Interest</h3> None declared