Birch pollen allergen-induced dsDNA release activates cGAS-STING signaling and type 2 immune response in mice

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-03-31 DOI:10.1016/j.isci.2025.112324

Pauline Chenuet , Manon Mellier , Yasmine Messaoud-Nacer , Elodie Culerier , Quentin Marquant , Louis Fauconnier , Nathalie Rouxel , Aurélie Ledru , Stéphanie Rose , Bernhard Ryffel , Lionel Apetoh , Valérie F.J. Quesniaux , Dieudonnée Togbe

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Abstract

Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.

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DNA 传感器环 GMP-AMP 合成酶（cGAS）和干扰素基因刺激器（STING）检测来自宿主或病原体的细胞质或细胞外 DNA 会触发免疫反应，分泌 I 型干扰素和炎症细胞因子。然而，STING 激动剂可作为促进过敏性哮喘的 2 型佐剂。在此，我们探讨了 cGAS/STING 信号通路如何影响桦树花粉提取物、屋尘螨或卵清蛋白加明矾诱导的过敏性气道疾病模型中过敏原诱导的 2 型免疫反应。我们报告了这些模型在受到过敏原挑战后气道中细胞外 dsDNA 的增加以及 cGAS 和 STING 基因的表达，并将 dsDNA 与 2 型细胞因子 IL-4、IL-5 和 IL-13 的释放联系起来。在 cGAS 或 STING 缺失的小鼠中，过敏原诱导的 2 型免疫反应减弱。此外，用特异性抑制剂 RU.521 阻断 cGAS 功能可保护小鼠免受桦树花粉过敏原诱发的气道炎症和 2 型免疫反应的影响。因此，cGAS的DNA感应有助于2型免疫反应，可能是过敏性肺部炎症的治疗靶点。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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