Hyperresponsive cytosolic DNA-sensing pathway in monocytes from primary Sjögren’s syndrome

Abstract

Objectives Cytosolic DNA-sensing pathway stimulation prompts type I IFN (IFN-I) production, but its role in systemic IFN-I pathway activation in primary SS (pSS) is poorly studied. Here, we investigate the responsiveness of pSS monocytes and plasmacytoid dendritic cells (pDCs) to STING activation in relation to systemic IFN-I pathway activation and compare this to SLE. Methods Expression of DNA-sensing receptors cGAS, IFI16, ZBP-1 and DDX41, signalling molecules STING, TBK1 and IRF3, positive and negative STING regulators, and IFN-I-stimulated genes MxA, IFI44, IFI44L, IFIT1, and IFIT3 was analysed in whole blood, CD14+ monocytes, pDCs, and salivary glands by RT-PCR, monocyte RNA-sequencing data, flow cytometry and immunohistochemical staining. Peripheral blood mononuclear cells (PBMCs) from pSS, SLE and healthy controls (HC) were stimulated with STING-agonist 2’3’-cGAMP. STING phopshorylation (pSTING) and intracellular IFNα were evaluated using flow cytometry. Results STING activation induced a significantly higher proportion of IFNα-producing monocytes—but not pDCs—in both IFN-low and IFN-high pSS compared with HC PBMCs. Additionally, a trend towards more pSTING+ monocytes was observed in pSS and SLE, most pronounced in IFN-high patients. Positive STING regulators TRIM38, TRIM56, USP18 and SENP7 were significantly higher expressed in pSS than HC monocytes, while the dual-function STING regulator RNF26 was downregulated in pSS monocytes. STING was expressed in mononuclear infiltrates and ductal epithelium in pSS salivary glands. STING stimulation induced pSTING and IFNα in pSS and SLE pDCs. Conclusion pSS monocytes and pDCs are hyperresponsive to stimulation of the STING pathway, which was not restricted to patients with IFN-I pathway activation.

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

“…Diseases such as subtypes of systemic lupus erythematosus (SLE), lupus nephritis (LN), and dermatomyositis, which have been suggested to be triggered by DNA viruses such as EBV, cytosolic dsDNA, or mitochondrial dsDNA, are also expected to be driven (at least in part) by the aberrant activation of cGAS. A prominent role of cGAS in the development of Sjogren’s Syndrome (SS) would not be unexpected since this disease shares many similarities with SLE; this has been confirmed by a recent publication showing hypersensitivity to cGAS/STING activators in SS patients [ 16 ].…”

Abnormal Changes of Monocyte Subsets in Patients With Sjögren’s Syndrome

“…Pertovaara et al found increased cytokine-induced STAT1 activation in monocytes of SjS patients via flow cytometry (44). Data from another 2 studies also supported the up-regulation of molecules related to the activation of IFN-related signaling in the monocytes of SjS patients (45,46). Therefore, there is good evidence supporting the up-regulation of IFN-related signaling in the monocytes of SjS patients.…”

“…Recent studies have proven the existence of distinct monocyte subsets and they have critical roles in the development of some rheumatic diseases such as SLE and rheumatoid arthritis (RA), and targeting monocytes is a potential treatment for those diseases (17,33). There are also some studies focusing on the roles of monocytes in SjS, and some have shown that aberrant changes in immunophenotypes, intracellular functional pathways and epigenetics exist in SjS patients (20)(21)(22)(23)(24). Those outcomes suggest the key roles of monocytes in the development and progression of SjS, though the underlying mechanisms are largely elusive.…”

“…For instance, monocytes can participate in the pathogenesis of SLE by immune mechanisms such as secreting pro-inflammatory cytokines and assisting in the activation of B cells and T cells (16)(17)(18)(19). In recent years, the roles of monocytes in the pathogenesis of SjS have also gained increased attentions, and some studies have proved possible key roles of monocytes in the development and progression of SjS (20)(21)(22)(23)(24). However, the mechanisms of monocytes in SjS have not been fully clarified, and further research is required.…”

Can the cGAS-STING Pathway Play a Role in the Dry Eye?

“…By sensing dsDNA, the cGAS-STING pathway has become a key pathway in autoimmune and inflammatory diseases (Table 1), such as Sjogren's syndrome (52), systemic lupus erythematosus (SLE) (45), and multiple sclerosis (53). As a downstream target of the cGAS-STING pathway, type I interferon serves as a marker and potential therapeutic target of systemic autoimmune diseases (54,55).…”