Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Given the primacy of Type I interferon (IFN) pathways in SLE pathogenesis, and the near-ubiquity of glucocorticoid (GC) use in SLE treatment, clarifying the intersection between these two domains is required. IFN activation in SLE appears largely GC-resistant, suggesting a permissive defect in GC-mediated regulatory events in SLE. GC-induced leucine zipper (GILZ) (TSC22D3) is one of the most exquisitely GC-sensitive genes in the genome, has endogenous effects which limit activation of T cells, B cells, macrophages and dendritic cells, but is underexpressed in SLE. We investigated the effect of GILZ on the IFN program in SLE.
Methods: Wildtype and GILZ deficient mice, and isolated cells, were stimulated using TLR ligands, and the effects of GILZ deficiency measured by qPCR, ELISA, Luminex, bioassay, and FACS. IFN effects on GILZ expression were studied in human PBMC and in public gene expression datasets. Mechanisms of regulation examined by ChIP.
Results: GILZ overexpression in human cells suppressed IFNα-induced gene expression. Conversely, loss of GILZ permitted unregulated expression of IFNs and other pro-inflammatory cytokines, including in vivo, in response to TLR ligands. GILZ directly suppressed TLR-stimulated expression of IRF7, the transcription factor that drives production of IFNα, by binding at the IRF7 locus. In parallel, IFNα suppressed GC induction of GILZ in PBMC, through direct binding of STAT1 at the GILZ promoter. Correspondingly, GILZ expression was significantly lower in IFN-positive SLE patients. Murine lupus and IFN activation were exacerbated when GILZ was deleted.
Conclusion: This work establishes GILZ as a key regulator of the IFN program that is in turn suppressed by IFN, a finding which may provide the explanation for GC resistance in high-IFN SLE. Restoring GILZ expression and activity represents a potential therapeutic opportunity to interrupt the IFN program in SLE, without the use of GC.
To cite this abstract in AMA style:Morand E, Nataraja C, Northcott M, Dankers W, Flynn J, Zhu W, Bennett T, Pervin M, Russ B, Harris J, Jones S. The Glucocorticoid-Induced Protein GILZ Represent a Checkpoint in the IFN Program in SLE [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/the-glucocorticoid-induced-protein-gilz-represent-a-checkpoint-in-the-ifn-program-in-sle/. Accessed February 18, 2020.
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