NET-derived DNA is associated with cGAS-STING and type I IFN responses, as supported by monocyte stimulation cultures using plasma from female patients with SLE.
4 affiliations
- 1Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, the Netherlands.
- 2Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, the Netherlands.
- 3Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, the Netherlands; Department of Internal Medicine, Flevo Hospital, Almere, the Netherlands.
- 4Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, the Netherlands; Department of Pediatrics, University Medical Center Utrecht, Utrecht University, the Netherlands. Electronic address: [email protected].
Abstract
Background
Neutrophil extracellular traps (NETs) are implicated in type I interferon (IFN) production in Systemic Lupus Erythematosus (SLE). While NETs are known to activate plasmacytoid dendritic cells (pDCs) via binding to Toll-like receptors, their effects on other immune cells remain underexplored. This study investigated whether NETs in plasma from patients with active SLE trigger cGAS-STING signalling in monocytes and induce the production of type I IFN and other immunomodulatory cytokines.Methods
Monocytes from healthy donors were cultured with diluted plasma from healthy donors or patients with SLE across varying disease activity, or with in vitro-generated NETs. Activation of the cGAS-STING pathway was assessed by flow cytometric analysis of phosphorylated STING (pSTING) and TBK1 (pTBK1). Cytokine production, including type I IFNs, was quantified using bead-based immunoassays. Only female donor samples meeting the study eligibility criteria were available for inclusion in this cohort.Findings
Plasma MPO-DNA levels correlated with IFNβ levels in patients with SLE (P = 0.002). SLE plasma induced STING and TBK1 phosphorylation, and IFNβ expression in healthy monocytes, with responses increasing according to donor disease activity (P < 0.0005). Experiments with healthy monocytes exposed to in vitro-generated NETs recapitulated these findings, evidenced by increased pSTING and pTBK1 expression and enhanced IFNα and IFNβ secretion (P < 0.05), which were inhibited by cGAS-IN-1.Interpretation
Our findings support a role for NET-associated DNA in activating cGAS-STING signalling and promoting type I IFN production by monocytes in SLE. These findings identify NET-mediated cGAS-STING signalling in monocytes as a pathway that warrants further investigation in the context of type I IFN-driven inflammation in SLE.Funding
Not Applicable.
Related
- Moderate pediatric burn injury is associated with reduced monocyte HLA-DR expression and heightened whole-blood LPS-induced TNF-α responses
- Developmental differences in platelet P-selectin expression modulate neonatal monocyte inflammatory responses
- Modeling the Relationship Between Stimulation Parameters and Motor Responses in PNS-TMS Paired Stimulation Using Gaussian Processes
- Transcutaneous auricular vagus nerve stimulation demonstrates effects on pupil responses in Parkinson's disease
- Monocyte-macrophage sensing of calciprotein particles in CKD-associated vascular calcification: lysosomal stress and inflammasome activation
BibTeX
@article{cao2026netderived,
title = {{NET-derived DNA is associated with cGAS-STING and type I IFN responses, as supported by monocyte stimulation cultures using plasma from female patients with SLE.}},
author = {Xiaolin Cao and Dagmar Duijzer and Tineke Kardol-Hoefnagel and Bettina C Geertsema-Hoeve and Jeanette H W Leusen and Maarten Limper and Marianne Boes},
journal = {EBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106507},
url = {https://europepmc.org/article/MED/42843114},
note = {CC BY},
}
RIS
TY - JOUR
TI - NET-derived DNA is associated with cGAS-STING and type I IFN responses, as supported by monocyte stimulation cultures using plasma from female patients with SLE.
AU - Xiaolin Cao
AU - Dagmar Duijzer
AU - Tineke Kardol-Hoefnagel
AU - Bettina C Geertsema-Hoeve
AU - Jeanette H W Leusen
AU - Maarten Limper
AU - Marianne Boes
PY - 2026
DA - 2026/10/07
JO - EBioMedicine
DO - 10.1016/j.ebiom.2026.106507
UR - https://europepmc.org/article/MED/42843114
AB - Background Neutrophil extracellular traps (NETs) are implicated in type I interferon (IFN) production in Systemic Lupus Erythematosus (SLE). While NETs are known to activate plasmacytoid dendritic cells (pDCs) via binding to Toll-like receptors, their effects on other immune cells remain underexplored. This study investigated whether NETs in plasma from patients with active SLE trigger cGAS-STING signalling in monocytes and induce the production of type I IFN and other immunomodulatory cytokines.Methods Monocytes from healthy donors were cultured with diluted plasma from healthy donors or patients with SLE across varying disease activity, or with in vitro-generated NETs. Activation of the cGAS-STING pathway was assessed by flow cytometric analysis of phosphorylated STING (pSTING) and TBK1 (pTBK1). Cytokine production, including type I IFNs, was quantified using bead-based immunoassays. Only female donor samples meeting the study eligibility criteria were available for inclusion in this cohort.Findings Plasma MPO-DNA levels correlated with IFNβ levels in patients with SLE (P = 0.002). SLE plasma induced STING and TBK1 phosphorylation, and IFNβ expression in healthy monocytes, with responses increasing according to donor disease activity (P < 0.0005). Experiments with healthy monocytes exposed to in vitro-generated NETs recapitulated these findings, evidenced by increased pSTING and pTBK1 expression and enhanced IFNα and IFNβ secretion (P < 0.05), which were inhibited by cGAS-IN-1.Interpretation Our findings support a role for NET-associated DNA in activating cGAS-STING signalling and promoting type I IFN production by monocytes in SLE. These findings identify NET-mediated cGAS-STING signalling in monocytes as a pathway that warrants further investigation in the context of type I IFN-driven inflammation in SLE.Funding Not Applicable.
SN - 2352-3964
ER -