Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice
Abstract Background Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflam...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-021-01763-3 |
| _version_ | 1829532037976948736 |
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| author | Atsushi Kurokawa Mitsuko Kondo Ken Arimura Shigeru Ashino Etsuko Tagaya |
| author_facet | Atsushi Kurokawa Mitsuko Kondo Ken Arimura Shigeru Ashino Etsuko Tagaya |
| author_sort | Atsushi Kurokawa |
| collection | DOAJ |
| description | Abstract Background Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. Methods In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. Results Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. Conclusions Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma. |
| first_indexed | 2024-12-16T18:32:10Z |
| format | Article |
| id | doaj.art-5cb405c041984c18a9c2aa13f2bd2b2e |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-12-16T18:32:10Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-5cb405c041984c18a9c2aa13f2bd2b2e2022-12-21T22:21:16ZengBMCRespiratory Research1465-993X2021-06-0122111210.1186/s12931-021-01763-3Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese miceAtsushi Kurokawa0Mitsuko Kondo1Ken Arimura2Shigeru Ashino3Etsuko Tagaya4Department of Respiratory Medicine, Tokyo Women’s Medical UniversityDepartment of Respiratory Medicine, Tokyo Women’s Medical UniversityDepartment of Respiratory Medicine, Tokyo Women’s Medical UniversityDepartment of Microbiology and Immunology, Tokyo Women’s Medical UniversityDepartment of Respiratory Medicine, Tokyo Women’s Medical UniversityAbstract Background Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. Methods In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. Results Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. Conclusions Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.https://doi.org/10.1186/s12931-021-01763-3Airway hyperresponsivenessAsthmaEosinophilsGoblet cell metaplasiaIL-33Innate immunity |
| spellingShingle | Atsushi Kurokawa Mitsuko Kondo Ken Arimura Shigeru Ashino Etsuko Tagaya Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice Respiratory Research Airway hyperresponsiveness Asthma Eosinophils Goblet cell metaplasia IL-33 Innate immunity |
| title | Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice |
| title_full | Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice |
| title_fullStr | Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice |
| title_full_unstemmed | Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice |
| title_short | Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice |
| title_sort | less airway inflammation and goblet cell metaplasia in an il 33 induced asthma model of leptin deficient obese mice |
| topic | Airway hyperresponsiveness Asthma Eosinophils Goblet cell metaplasia IL-33 Innate immunity |
| url | https://doi.org/10.1186/s12931-021-01763-3 |
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