Manipulation of dipeptidylpeptidase 10 in mouse and human and models indicates a protective role in asthma.

Zhang, Youming and Poobalasingam, Thanushiyan and Yates, Laura L and Walker, Simone A and Taylor, Martin S and Chessum, Lauren and Harrison, Jackie and Tsaprouni, Loukia and Adcock, Ian M and Lloyd, Clare M and Cookson, William O and Moffatt, Miriam F and Dean, Charlotte H (2018) Manipulation of dipeptidylpeptidase 10 in mouse and human and models indicates a protective role in asthma. Disease models & mechanisms, 11 (1). ISSN 1754-8411

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Abstract

We previously identified dipeptidylpeptidase 10 () on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established ( ). Macroscopic examination and lung histology revealed no significant differences between wild-type and mice. However, after house dust mite (HDM) treatment, mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of in human airway epithelial cells results in altered cytokine responses. These results show that a point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies. This article has an associated First Person interview with the first author of the paper.

Item Type: Article
Subjects: C100 Biology
Divisions: Faculty of Health, Education and Life Sciences > School of Health Sciences
Depositing User: Loukia Tsaprouni
Date Deposited: 01 May 2018 08:59
Last Modified: 01 May 2018 08:59
URI: http://www.open-access.bcu.ac.uk/id/eprint/5845

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