Advertisement

ResearchIn-Press PreviewImmunologyInflammationPulmonology Open Access | 10.1172/JCI187907

Allergens abrogate anti-inflammatory DNA effects and unmasks macrophage-driven neutrophilic asthma via ILC2/STING/TNFα signaling

Anand Sripada,1 Divya Verma,1 Rangati Varma,1 Kapil Sirohi,1 Carolyn Kwiat,1 Mohini Pathria,1 Mukesh Verma,1 Anita Sahu,1 Vamsi P. Guntur,2 Laurie A. Manka,2 Brian Vestal,3 Camille M. Moore,3 Richard J. Martin,2 Magdalena M. Gorska,1 John Cambier,4 Andrew Getahun,4 and Rafeul Alam1

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Sripada, A. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Verma, D. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Varma, R. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Sirohi, K. in: PubMed | Google Scholar |

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Kwiat, C. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Pathria, M. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Verma, M. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Sahu, A. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Guntur, V. in: PubMed | Google Scholar |

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Manka, L. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Vestal, B. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Moore, C. in: PubMed | Google Scholar |

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Martin, R. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Gorska, M. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Cambier, J. in: PubMed | Google Scholar

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Getahun, A. in: PubMed | Google Scholar |

1Division of Allergy & Immunology, National Jewish Health, Denver, United States of America

2Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, United States of America

3Department of Immunology & Genomic Medicine, National Jewish Health, Denver, United States of America

4Department of Immunology and Microbiology, University of Colorado Denver, Denver, United States of America

Find articles by Alam, R. in: PubMed | Google Scholar

Published June 17, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187907.
Copyright © 2025, Sripada et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 17, 2025 - Version history
View PDF
Abstract

The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (June 17, 2025): In-Press Preview
Advertisement
Advertisement