STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite

• Published in: Allergy (Copenhagen)
• Main Authors: Messaoud-Nacer, Yasmine, Culerier, Elodie, Rose, Stéphanie, Maillet, Isabelle, Boussad, Rania, Veront, Chloé, Savigny, Florence, Malissen, Bernard, Radzikowska, Urszula, Sokolowska, Milena, da Silva, Gabriel V L, Edwards, Michael R, Jackson, David J, Johnston, Sebastian L, Ryffel, Bernhard, Quesniaux, Valerie F, Togbe, Dieudonnée
• Format: Journal Article
• Language: English
• Published: Denmark Wiley 28.10.2024
• Subjects: Life Sciences; asthma exacerbation; with inserts; cGAMP; cell death; DNA sensing; diABZI; MLKL: Mixed Lineage Kinase domain Likepseudokinase; BronchoAlveolar Lavage Fluid; hAEC; DNA sensing, cGAMP, diABZI, cell death, asthma exacerbation airway hyperresponsiveness, AIM2: absent in melanoma 2, BAL, BronchoAlveolar Lavage; GSDMD: Gasdermin Gene Expression Omnibus; cGAMP: cyclic Guanosine monophosphate-Adenosine MonoPhosphate; diABZI: symmetry-related amidobenzimidazole-based compounds; MPO: myeloperoxidase; BALF, BronchoAlveolar Lavage Fluid; BronchoAlveolar Lavage Fluid cGAMP: cyclic Guanosine monophosphate-Adenosine MonoPhosphate; LDH: Lactate DeHydrogenase; HE: hematoxylin and eosin; human airway epithelial cells; HDM: house dust mite; AIM2: absent in melanoma 2; BronchoAlveolar Lavage; DNA sensing, cGAMP, diABZI, cell death, asthma exacerbation airway hyperresponsiveness, AIM2: absent in melanoma 2, BAL, BronchoAlveolar Lavage BALF, BronchoAlveolar Lavage Fluid cGAMP: cyclic Guanosine monophosphate-Adenosine MonoPhosphate, cGAS: cyclic GMP-AMP synthase, DDX41: DEAD-box helicase 41, diABZI: symmetry-related amidobenzimidazole-based compounds, GSDMD: Gasdermin Gene Expression Omnibus, hAEC, human airway epithelial cells, HBEC: human bronchial epithelial cells, HDM: house dust mite, HE: hematoxylin and eosin, IFI204: IFN--Inducible protein 204, IRF3: IFN regulatory factor 3, ISG: Interferon Stimulated Gene, LDH Lactate DeHydrogenase, MLKL: Mixed Lineage Kinase domain Likepseudokinase, MPO: myeloperoxidase, NETs: Neutrophil Extracellular Traps, NLRP3: NOD-, LRR-and Pyrin Domain-Containing Protein 3, PAS: Periodic acid Schiff, RNA-Seq : RNA sequencing; IFI204: IFN--Inducible protein 204; BALF; BronchoAlveolar Lavage BALF; NLRP3: NOD; asthma exacerbation airway hyperresponsiveness; PAS: Periodic acid Schiff; cGAMP: cyclic Guanosine monophosphate-Adenosine MonoPhosphate, cGAS: cyclic GMP-AMP synthase, DDX41: DEAD-box helicase 41, diABZI: symmetry-related amidobenzimidazole-based compounds, GSDMD: Gasdermin Gene Expression Omnibus, hAEC, human airway epithelial cells, HBEC: human bronchial epithelial cells, HDM: house dust mite, HE: hematoxylin and eosin, IFI204: IFN--Inducible protein 204, IRF3: IFN regulatory factor 3, ISG: Interferon Stimulated Gene, LDH Lactate DeHydrogenase, MLKL: Mixed Lineage Kinase domain Likepseudokinase, MPO: myeloperoxidase, NETs: Neutrophil Extracellular Traps, NLRP3: NOD-, LRR-and Pyrin Domain-Containing Protein 3, PAS: Periodic acid Schiff, RNA-Seq : RNA sequencing; BAL; HBEC: human bronchial epithelial cells; ISG: Interferon Stimulated Gene; RNA-Seq : RNA sequencing; DDX41: DEAD-box helicase 41; IRF3: IFN regulatory factor 3; cGAS: cyclic GMP-AMP synthase; LRR-and Pyrin Domain-Containing Protein 3; NETs: Neutrophil Extracellular Traps
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.16369

Severe refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING-induced neutrophilic lung inflammation mimics severe asthma. We developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild-type, and conditional-STING-deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma. DiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2 ARG1 type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL-6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA-sensing and PANoptosis pathways upregulation and tight-junction downregulation induced by rhinovirus challenge in patients with asthma. Our study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils.