Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice
BackgroundExtra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious...
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1252874/full |
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| author | Verena M. Merk Truong San Phan Truong San Phan Alice Wiedmann Rowan S. Hardy Gareth G. Lavery Thomas Brunner |
| author_facet | Verena M. Merk Truong San Phan Truong San Phan Alice Wiedmann Rowan S. Hardy Gareth G. Lavery Thomas Brunner |
| author_sort | Verena M. Merk |
| collection | DOAJ |
| description | BackgroundExtra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1/Hsd11b1)-dependent local GC reactivation in the regulation of allergic airway inflammation.MethodsAirway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11β-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, ex vivo tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting.ResultsHere we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC ex vivo compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response.ConclusionWe propose an important role of 11β-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells. |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T16:43:50Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-f2db5356f93f4035922c09efc1c98a242023-10-23T07:34:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12528741252874Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in miceVerena M. Merk0Truong San Phan1Truong San Phan2Alice Wiedmann3Rowan S. Hardy4Gareth G. Lavery5Thomas Brunner6Department of Biology, University of Konstanz, Konstanz, GermanyDepartment of Biology, University of Konstanz, Konstanz, GermanyDepartment of Systems Immunology, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biology, University of Konstanz, Konstanz, GermanyInstitute of Clinical Sciences, University of Birmingham, Birmingham, United KingdomDepartment of Biosciences, Nottingham Trent University, Nottingham, United KingdomDepartment of Biology, University of Konstanz, Konstanz, GermanyBackgroundExtra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1/Hsd11b1)-dependent local GC reactivation in the regulation of allergic airway inflammation.MethodsAirway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11β-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, ex vivo tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting.ResultsHere we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC ex vivo compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response.ConclusionWe propose an important role of 11β-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1252874/fullglucocorticoidscorticosteroids11β-hydroxysteroid dehydrogenase 1lunghouse dust miteairway hypersensitivity |
| spellingShingle | Verena M. Merk Truong San Phan Truong San Phan Alice Wiedmann Rowan S. Hardy Gareth G. Lavery Thomas Brunner Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice Frontiers in Immunology glucocorticoids corticosteroids 11β-hydroxysteroid dehydrogenase 1 lung house dust mite airway hypersensitivity |
| title | Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice |
| title_full | Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice |
| title_fullStr | Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice |
| title_full_unstemmed | Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice |
| title_short | Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice |
| title_sort | local glucocorticoid synthesis regulates house dust mite induced airway hypersensitivity in mice |
| topic | glucocorticoids corticosteroids 11β-hydroxysteroid dehydrogenase 1 lung house dust mite airway hypersensitivity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1252874/full |
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