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变应原通过ILC2/STING/TNF-α信号通路消除抗炎性DNA效应并揭示巨噬细胞驱动的嗜中性粒细胞性哮喘。

Allergens abrogate antiinflammatory DNA effects and unmask macrophage-driven neutrophilic asthma via ILC2/STING/TNF-α signaling.

作者信息

Sripada Anand, Verma Divya, Varma Rangati, Sirohi Kapil, Kwiat Carolyn, Pathria Mohini, Verma Mukesh, Sahu Anita, Guntur Vamsi, Manka Laurie, Vestal Brian, Moore Camille, Martin Richard J, Gorska Magdalena M, Cambier John, Getahun Andrew, Alam Rafeul

机构信息

Division of Allergy & Immunology.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, National Jewish Health, Denver, Colorado, USA.

出版信息

J Clin Invest. 2025 Jun 17;135(16). doi: 10.1172/JCI187907. eCollection 2025 Aug 15.

DOI:10.1172/JCI187907
PMID:40526428
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12352889/
Abstract

The mechanisms of neutrophilic and mixed neutrophilic-eosinophilic asthma are poorly understood. We found that extracellular DNA and nucleosomes (Nucs) were elevated in the airways of patients with neutrophilic-eosinophilic asthma and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma had more DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when coadministered with the allergen Alternaria (Alt). Nuc alone induced antiinflammatory/defensive genes, whereas the Nuc-Alt combination increased levels of TNF-α and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingfl/fl, IL7RCre:Rorαfl/fl, and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc induction of antiinflammatory genes, facilitated Nuc uptake, induced type 2 innate lymphoid cells, which, in the presence of Nuc, produced high levels of TNF-α, and promoted neutrophilic infiltration. We established a paradigm whereby allergens inhibit the antiinflammatory effects of DNA/Nuc and facilitate STING-TNF-α-driven neutrophilic-eosinophilic inflammation in asthma.

摘要

中性粒细胞性和中性粒细胞-嗜酸性粒细胞混合性哮喘的发病机制尚不清楚。我们发现，中性粒细胞-嗜酸性粒细胞性哮喘患者气道中的细胞外DNA和核小体（Nucs）水平升高，且与支气管肺泡灌洗中性粒细胞相关。中性粒细胞-嗜酸性粒细胞性哮喘患者的支气管组织中有更多DNA传感器阳性细胞。经鼻给予DNA不会诱发气道高反应性（AHR）或任何病理变化，但与变应原链格孢菌（Alt）共同给药时会诱发AHR和中性粒细胞-嗜酸性粒细胞性炎症。单独的Nuc可诱导抗炎/防御基因，而Nuc与Alt的组合会增加TNF-α和固有细胞因子的水平。在Cgas-/-、ALR-/-、Sting-/-、LysMCre:Stingfl/fl、IL7RCre:Rorαfl/fl和Tnfr2-/-小鼠中，Alt-Nuc表型消失。出乎意料的是，Alt在Nuc诱导的表型中起关键作用。它消除了Nuc对抗炎基因的诱导作用，促进了Nuc的摄取，诱导了2型固有淋巴细胞，在Nuc存在的情况下，这些细胞产生高水平的TNF-α，并促进中性粒细胞浸润。我们建立了一种模式，即变应原抑制DNA/Nuc的抗炎作用，并促进哮喘中由STING-TNF-α驱动的中性粒细胞-嗜酸性粒细胞性炎症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/d0a2d75dc2ff/jci-135-187907-g044.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/72aa71e0ede7/jci-135-187907-g037.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/e6afe93e4dfb/jci-135-187907-g038.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/0bf16edf7ee0/jci-135-187907-g039.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/a9a0bf7856f1/jci-135-187907-g040.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/83b0e76d5e1c/jci-135-187907-g041.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/c6503e0d6d83/jci-135-187907-g042.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/213e043d7f5a/jci-135-187907-g043.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/d0a2d75dc2ff/jci-135-187907-g044.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/72aa71e0ede7/jci-135-187907-g037.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/e6afe93e4dfb/jci-135-187907-g038.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/0bf16edf7ee0/jci-135-187907-g039.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/a9a0bf7856f1/jci-135-187907-g040.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/83b0e76d5e1c/jci-135-187907-g041.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/c6503e0d6d83/jci-135-187907-g042.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/213e043d7f5a/jci-135-187907-g043.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/619f/12352889/d0a2d75dc2ff/jci-135-187907-g044.jpg

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