Background/Purpose: Systemic lupus erythematosus (SLE) is a heterogenous systemic autoimmune disease which is associated with innate immune activation, type I IFN, inflammasome and NFkB-related cytokines. Several innate signaling pathways including TLRs, STING, IFN, RIG-I and MDA5 are reported to be actively involved in the pathogenesis of SLE, although the relative contribution of these pathways to disease activity and pathology across the SLE patient population remains uncertain. 

The objective of this study is to ascertain which of innate signaling pathways play a critical role in driving inflammatory mediators in SLE patients.

Methods: We characterized healthy and lupus patient serum for innate immune pathway-specific type I IFN and NFkB activation activity using myeloid dual reporter THP1 cells lines.  Reporter cell lines with knockouts of specific innate immune receptors (including MyD88, STING, IFNAR, RIG-I, MDA5, TLR or IRF3/5/7 transcription factors) were treated with innate pathway specific agonists/antagonists or donor sera to examine type I IFN and NFkB activity. We then analyzed the composition of donor sera by measuring 120 autoantibodies and 250 autoimmune-associated secretory proteins using Systemic Autoimmune-associated Antigen Array (Genecopoeia) and NULISAseq (Alamar Biosciences), respectively.  Statistical correlations were made between serum innate immune pathway-specific activity of IFN and NFkB responses to autoimmune protein and autoantibody levels.

Results: SLE serum had high type I IFN and NFkB activating activity that could be inhibited to varying degrees by specific innate receptor knockout. As expected the IFNAR pathway knockout was the most effective at inhibiting the type I IFN response, but it did not inhibit lupus serum induced NFkB responses. The STING and MyD88 knockout were the strongest inhibitors of SLE serum induced NFkB responses, while suppressing >50% of the type I IFN response. In contrast, RIG1 and IRF knockout were not effective in inhibiting the response. Several elevated autoantibodies levels that correlate significantly with STING pathway-specific activity of serum including dsDNA, core histone, complement factor P, and collagen XVIIa. STING pathway activity also positively associated with a unique autoimmune protein signature in patients including IL-27, IL-17A, IL-18, CCL4, VEGFA, IL-1RN, CTSS, and EGF.

Conclusion: This study reveals that STING pathway mediates a major portion of the innate immune driven NFkB and IFN activity in lupus patient serum, and positively associates with the levels of a subset of autoantibodies and a unique patient cytokine profile. Comparison of several innate pathways indicates that STING pathway activity is one of the most broadly acting and correlative to lupus serum induced innate immune mediated SLE activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sting-pathway-activity-in-sle-patient-serum-correlates-with-nfkb-activation-autoantibody-levels-and-a-unique-cytokine-profile-that-drives-disease-activity/