Exploring cGAS-STING Pathway in Sjögren’s Disease: Driver of IFN production and Potential Therapeutic Target

Authors

• E Yamada
• M Abed
• P Perez
• S Jang
• T Pranzatelli
• J Chiorini
• B Warner

Abstract

Sjögren’s Disease (SjD) is a common systemic autoimmune disease without effective therapy or cure. Despite unknown pathogenic mechanisms, dysregulated Type-I interferon (IFN) signaling is common in SjD patients. Type-I IFN drivers are not elucidated; recent evidence has implicated cGAS-STING pathway in systemic lupus patients. We aimed to better understand the pathogenetic drivers of Type-I IFN in SjD focusing on cGAS-STING pathway hypothesized that cGAS-STING pathway is activated in SjD and contributing to both local/systemic symptoms and IFNs dysregulation. RNAseq of paired blood and salivary gland (SG) biopsies exhibited significantly increased IFNs scores and correlations with lymphocytic inflammation in SjD SG. Single cell (sc) RNAseq, immunofluorescence microscopy, and conventional flow-cytometry showed higher IFN scores in epithelial/inflammatory cells, increased STING and a downstream target of STING expression in acini/ducts/inflammatory-infiltrates, indicating upregulated signaling in SjD. Flow-cytometry demonstrated phosphorylated-cGAS-STING pathway proteins were elevated in SjD SG and these levels were directly correlated with immune cells infiltration, suggesting inflammatory-infiltrates in SG could be key pathogenetic cGAS-STING drivers. Similar to SG, scRNAseq of SjD peripheral blood mononuclear cells (PBMC) indicated IFN expression correlates with cGAS-STING pathway utilization in specific cell types. 35-color spectral flow-cytometry of PBMC demonstrated basal levels of cGAS-STING related total-/phospho-proteins were upregulated in SjD. We also confirmed H-151, a commercially available STING antagonist, was able to reduce phospho-protein levels without cytotoxicity in SG/PBMC. Taken together, targeting cGAS-STING has the potential to mitigate drivers of systemic and salivary gland inflammation and prevent damaging secondary effects of chronic inflammation including exocrine hypofunction and tissue destruction.

Scientific Focus Area: Immunology

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