STING Mediates Lupus via the Activation of Conventional Dendritic Cell Maturation and Plasmacytoid Dendritic Cell Differentiation
Arthid Thim-uam,
Thaneas Prabakaran,
Mookmanee Tansakul,
Jiradej Makjaroen,
Piriya Wongkongkathep,
Naphat Chantaravisoot,
Thammakorn Saethang,
Asada Leelahavanichkul,
Thitima Benjachat,
Søren Paludan,
Trairak Pisitkun,
Prapaporn Pisitkun
Affiliations
Arthid Thim-uam
Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand; Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Thaneas Prabakaran
Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark
Mookmanee Tansakul
Section for Translational Medicine Program, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama 6 Road, Ratchathewi, Bangkok 10400, Thailand
Jiradej Makjaroen
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Piriya Wongkongkathep
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Naphat Chantaravisoot
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand; Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Thammakorn Saethang
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Asada Leelahavanichkul
Center of Excellence in Immunology and Immune-mediated Diseases, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Thitima Benjachat
Center of Excellence in Immunology and Immune-mediated Diseases, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
Søren Paludan
Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark
Trairak Pisitkun
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand; Epithelial Systems Biology Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Corresponding author
Prapaporn Pisitkun
Section for Translational Medicine Program, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama 6 Road, Ratchathewi, Bangkok 10400, Thailand; Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama 6 Road, Ratchathewi, Bangkok 10400, Thailand; Corresponding author
Summary: Signaling through stimulator of interferon genes (STING) leads to the production of type I interferons (IFN-Is) and inflammatory cytokines. A gain-of-function mutation in STING was identified in an autoinflammatory disease (STING-associated vasculopathy with onset in infancy; SAVI). The expression of cyclic GMP-AMP, DNA-activated cGAS-STING pathway, increased in a proportion of patients with SLE. The STING signaling pathway may be a candidate for targeted therapy in SLE. Here, we demonstrated that disruption of STING signaling ameliorated lupus development in Fcgr2b-deficient mice. Activation of STING promoted maturation of conventional dendritic cells and differentiation of plasmacytoid dendritic cells via LYN interaction and phosphorylation. The inhibition of LYN decreased the differentiation of STING-activated dendritic cells. Adoptive transfer of STING-activated bone marrow-derived dendritic cells into the FCGR2B and STING double-deficiency mice restored lupus phenotypes. These findings provide evidence that the inhibition of STING signaling may be a candidate targeted treatment for a subset of patients with SLE.