EBioMedicine · 2026
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.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Cao Xiaolin, Duijzer Dagmar, Kardol-Hoefnagel Tineke, Geertsema-Hoeve Bettina C, Leusen Jeanette H W, Limper Maarten, Boes Marianne
Аннотация
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.
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.