Characterization and inhibition of inflammasome responses in severe and non-severe asthma
Abstract Background Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflamm...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02603-2 |
| _version_ | 1827590346897358848 |
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| author | Jay C. Horvat Richard Y. Kim Natasha Weaver Christopher Augood Alexandra C. Brown Chantal Donovan Pierrick Dupre Lakshitha Gunawardhana Jemma R. Mayall Nicole G. Hansbro Avril A. B. Robertson Luke A. J. O’Neill Matthew A. Cooper Elizabeth G. Holliday Philip M. Hansbro Peter G. Gibson |
| author_facet | Jay C. Horvat Richard Y. Kim Natasha Weaver Christopher Augood Alexandra C. Brown Chantal Donovan Pierrick Dupre Lakshitha Gunawardhana Jemma R. Mayall Nicole G. Hansbro Avril A. B. Robertson Luke A. J. O’Neill Matthew A. Cooper Elizabeth G. Holliday Philip M. Hansbro Peter G. Gibson |
| author_sort | Jay C. Horvat |
| collection | DOAJ |
| description | Abstract Background Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. Objective To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed. Results PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups. Conclusion An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease. |
| first_indexed | 2024-03-09T01:15:36Z |
| format | Article |
| id | doaj.art-60288ffe24fd40148d0b5a1960f9d444 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-09T01:15:36Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-60288ffe24fd40148d0b5a1960f9d4442023-12-10T12:29:00ZengBMCRespiratory Research1465-993X2023-12-0124111410.1186/s12931-023-02603-2Characterization and inhibition of inflammasome responses in severe and non-severe asthmaJay C. Horvat0Richard Y. Kim1Natasha Weaver2Christopher Augood3Alexandra C. Brown4Chantal Donovan5Pierrick Dupre6Lakshitha Gunawardhana7Jemma R. Mayall8Nicole G. Hansbro9Avril A. B. Robertson10Luke A. J. O’Neill11Matthew A. Cooper12Elizabeth G. Holliday13Philip M. Hansbro14Peter G. Gibson15University of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteCentenary Institute, Centre for Inflammation, and University of Technology Sydney, Faculty of Science, School of Life SciencesThe University of Queensland, School of Chemistry and Molecular BiosciencesTrinity College Dublin, Trinity Biomedical Sciences Institute, School of Biochemistry and ImmunologySitala Bio Ltd.University of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteUniversity of Newcastle and Hunter Medical Research InstituteAbstract Background Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. Objective To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed. Results PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups. Conclusion An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.https://doi.org/10.1186/s12931-023-02603-2AsthmaSevere asthmaNLRP3 inflammasomeIL-1βInflammasome inhibition |
| spellingShingle | Jay C. Horvat Richard Y. Kim Natasha Weaver Christopher Augood Alexandra C. Brown Chantal Donovan Pierrick Dupre Lakshitha Gunawardhana Jemma R. Mayall Nicole G. Hansbro Avril A. B. Robertson Luke A. J. O’Neill Matthew A. Cooper Elizabeth G. Holliday Philip M. Hansbro Peter G. Gibson Characterization and inhibition of inflammasome responses in severe and non-severe asthma Respiratory Research Asthma Severe asthma NLRP3 inflammasome IL-1β Inflammasome inhibition |
| title | Characterization and inhibition of inflammasome responses in severe and non-severe asthma |
| title_full | Characterization and inhibition of inflammasome responses in severe and non-severe asthma |
| title_fullStr | Characterization and inhibition of inflammasome responses in severe and non-severe asthma |
| title_full_unstemmed | Characterization and inhibition of inflammasome responses in severe and non-severe asthma |
| title_short | Characterization and inhibition of inflammasome responses in severe and non-severe asthma |
| title_sort | characterization and inhibition of inflammasome responses in severe and non severe asthma |
| topic | Asthma Severe asthma NLRP3 inflammasome IL-1β Inflammasome inhibition |
| url | https://doi.org/10.1186/s12931-023-02603-2 |
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