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Less Airway Inflammation and Goblet Cell Metaplasia in an IL-33-Induced Asthma Model of Leptin-Deficient Obese Mice
Mitsuko Kondo
Tokyo Women's Medical University: Tokyo Joshi Ika Daigaku
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3673-5431
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Asthma with obesity is a phenotype of severe asthma. Leptin exerts an immunomodulatory effect and its level is increased in obesity. IL-33 is associated with innate immunity and induces type 2 inflammation, and is present in adipose tissue. However, the role of IL-33 and leptin in obesity-associated asthma is not fully understood. We examined the effect of IL-33 on eosinophilic inflammation, goblet cell metaplasia, and airway responsiveness in leptin-deficient obese (ob/ob) and wild-type mice, and examined the effect of exogenous leptin pretreatment.
Methods
In ob/ob and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the animals, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine and resistance of the respiratory system (Rrs) was measured using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, 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, and MUC5AC levels were measured by ELISA.
Results
Ob/ob mice showed greater baseline Rrs than wild-type mice. IL-33 and IL-33 with leptin did not enhance Rrs challenged with methacholine compared to non-treatment in ob/ob mice, whereas IL-33 with leptin enhanced Rrs in wild-type mice. Ob/ob mice showed less IL-33-induced eosinophil numbers, IL-5, IL-13, eotaxin, and KC levels in BALF and eosinophilic infiltration around bronchi and goblet cell metaplasia than wild-type mice, but leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro .
Conclusions
Leptin plays an important role in IL-33-induced inflammation and goblet cell metaplasia in the airway, but obesity per se increases airway hyperresponsiveness independent of inflammation. These results explain some aspects of the pathogenesis of obesity-related asthma.
Keywords
asthma, obesity, eosinophils, goblet cell metaplasia, innate immunity
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CURRENT STATUS: Under Revision
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Posted 28 Sep, 2020
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Editorial decision: Major revision
On 09 Nov, 2020
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Received 08 Nov, 2020
Review #2 received
Received 08 Nov, 2020
Reviewer #3 agreed
On 27 Oct, 2020
Reviewer #2 agreed
On 26 Oct, 2020
Review #1 received
Received 19 Oct, 2020
Reviewers invited
Invitations sent on 05 Oct, 2020
Reviewer #1 agreed
On 05 Oct, 2020
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On 23 Sep, 2020
First submitted
On 22 Sep, 2020
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On 22 Sep, 2020
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This preprint is under consideration at Respiratory Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Less Airway Inflammation and Goblet Cell Metaplasia in an IL-33-Induced Asthma Model of Leptin-Deficient Obese Mice
Mitsuko Kondo
Tokyo Women's Medical University: Tokyo Joshi Ika Daigaku
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3673-5431
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 28 Sep, 2020
No community comments so far
Editorial decision: Major revision
On 09 Nov, 2020
Review #3 received
Received 08 Nov, 2020
Review #2 received
Received 08 Nov, 2020
Reviewer #3 agreed
On 27 Oct, 2020
Reviewer #2 agreed
On 26 Oct, 2020
Review #1 received
Received 19 Oct, 2020
Reviewers invited
Invitations sent on 05 Oct, 2020
Reviewer #1 agreed
On 05 Oct, 2020
Editor assigned
On 23 Sep, 2020
First submitted
On 22 Sep, 2020
Submission checks complete
On 22 Sep, 2020
Editor invited
On 22 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Asthma with obesity is a phenotype of severe asthma. Leptin exerts an immunomodulatory effect and its level is increased in obesity. IL-33 is associated with innate immunity and induces type 2 inflammation, and is present in adipose tissue. However, the role of IL-33 and leptin in obesity-associated asthma is not fully understood. We examined the effect of IL-33 on eosinophilic inflammation, goblet cell metaplasia, and airway responsiveness in leptin-deficient obese (ob/ob) and wild-type mice, and examined the effect of exogenous leptin pretreatment.
Methods
In ob/ob and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the animals, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine and resistance of the respiratory system (Rrs) was measured using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, 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, and MUC5AC levels were measured by ELISA.
Results
Ob/ob mice showed greater baseline Rrs than wild-type mice. IL-33 and IL-33 with leptin did not enhance Rrs challenged with methacholine compared to non-treatment in ob/ob mice, whereas IL-33 with leptin enhanced Rrs in wild-type mice. Ob/ob mice showed less IL-33-induced eosinophil numbers, IL-5, IL-13, eotaxin, and KC levels in BALF and eosinophilic infiltration around bronchi and goblet cell metaplasia than wild-type mice, but leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro .
Conclusions
Leptin plays an important role in IL-33-induced inflammation and goblet cell metaplasia in the airway, but obesity per se increases airway hyperresponsiveness independent of inflammation. These results explain some aspects of the pathogenesis of obesity-related asthma.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.