TY - JOUR
T1 - Hyperresponsive cytosolic DNA-sensing pathway in monocytes from primary Sjögren's syndrome
AU - Huijser, Erika
AU - Bodewes, Iris L.A.
AU - Lourens, Mirthe S.
AU - Van Helden-Meeuwsen, Cornelia G.
AU - Van Den Bosch, Thierry P.P.
AU - Grashof, Dwin G.B.
AU - Van De Werken, Harmen J.G.
AU - Lopes, Ana P.
AU - Van Roon, Joel A.G.
AU - Van Daele, Paul L.A.
AU - Brkic, Zana
AU - Dik, Willem A.
AU - Versnel, Marjan A.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the British Society for Rheumatology.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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 stimulator of interferon genes (STING) activation in relation to systemic IFN-I pathway activation and compare this with 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 (HCs) were stimulated with STING agonist 2′3′-cGAMP. STING phosphorylation (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 expression 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.
AB - 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 stimulator of interferon genes (STING) activation in relation to systemic IFN-I pathway activation and compare this with 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 (HCs) were stimulated with STING agonist 2′3′-cGAMP. STING phosphorylation (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 expression 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.
KW - DNA-sensing pathway
KW - monocytes
KW - Sjögren's syndrome
KW - STING
KW - type I IFN
UR - http://www.scopus.com/inward/record.url?scp=85127088338&partnerID=8YFLogxK
U2 - 10.1093/rheumatology/keac016
DO - 10.1093/rheumatology/keac016
M3 - Article
C2 - 35022662
AN - SCOPUS:85127088338
SN - 1462-0324
VL - 61
SP - 3491
EP - 3496
JO - Rheumatology (United Kingdom)
JF - Rheumatology (United Kingdom)
IS - 8
ER -