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桦树花粉过敏原诱导的双链DNA释放激活小鼠体内的cGAS-STING信号通路和2型免疫反应。

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

作者信息

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

机构信息

Artimmune SAS, 13 Avenue Buffon, 45100 Orléans, France.

Laboratory of Immuno-Neuro Modulation (INEM), UMR 7355 CNRS and University of Orleans, 3B rue de la Ferollerie, 45071 Orleans-Cedex, France.

出版信息

iScience. 2025 Mar 31;28(5):112324. doi: 10.1016/j.isci.2025.112324. eCollection 2025 May 16.

DOI:10.1016/j.isci.2025.112324
PMID:40276777
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12018559/
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.

摘要

DNA传感器环磷酸鸟苷-腺苷合成酶（cGAS）和干扰素基因刺激因子（STING）检测来自宿主或病原体的细胞质或细胞外DNA，通过分泌I型干扰素和炎性细胞因子触发免疫反应。然而，STING激动剂作为2型佐剂促进过敏性哮喘。在此，我们研究了在桦树花粉提取物、屋尘螨或卵清蛋白加明矾诱导的过敏性气道疾病模型中，cGAS/STING信号通路如何影响变应原诱导的2型免疫反应。我们报告，在这些模型中，变应原激发后气道中细胞外双链DNA增加，同时伴有cGAS和STING基因表达，双链DNA与2型细胞因子白细胞介素-4、白细胞介素-5和白细胞介素-13的释放相关。在cGAS或STING缺陷小鼠中，变应原诱导的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变应原诱导的气道炎症和2型免疫反应。因此，cGAS介导的DNA传感促成2型免疫反应，可能是过敏性肺部炎症的一个治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/d0cf3a36768f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/4b8605370d59/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/59e6a599c693/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/69eee84dab22/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/d5d1a07c9f8a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/d0cf3a36768f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/4b8605370d59/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/59e6a599c693/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/69eee84dab22/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/d5d1a07c9f8a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfac/12018559/d0cf3a36768f/gr4.jpg

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