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

Abstract

We previously identified dipeptidylpeptidase 10 (DPP10) 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 Dpp10 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 (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 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 DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 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.

Novel computational analysis of large transcriptome datasets identifies sets of genes distinguishing chronic obstructive pulmonary disease from healthy lung samples

“…Kv4 channels are also expressed apically by alveolar epithelial cells and are hypothesised to play a role in potassium secretion or oxygen sensing 30 . Structural and functional DPP6 homologue DPP10 is associated with asthma 31 FRAS1 related extracellular matrix 3 FREM3 Down Associated with accelerated aging 32 in a non-COPD context Polypeptide N-acetylgalactosaminyltransferase 14 GALNT14 Down – Pyroglutamylated RFamide peptide receptor QRFPR Down – …”

Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

“…Additionally, polymorphisms of DPP10 were associated with asthma and related traits 59 . Zhang Y et al 51 showed that HDM‐induced AHR and airway inflammation in DPP10 mutant mice were more severe than in wild‐type mice, providing in vivo evidence supporting the protective role of DPP10 in regulation of asthma severity. Among the 816 DMPs, we also found that three DMPs had the greatest values in the prediction of asthma severity in children.…”

“…Fifty‐nine genes have multiple DMPs (≥2). Several of these genes, including LTB4R2 , 50 DPP10 , 51 IL17RA , 52 CYFIP2 , 53 DNAH5 , 54 MRPL28 , 55 and PTPRN2 , 56 are critical in different aspects of asthma. Among genes associated with the DMRs, LTB4R2 is essential for leukotriene B4 (LTB4) synthesis.…”

Long non‐coding RNA and mRNA expression profiles in peri‐implantitis vs periodontitis

“…The CNC network analysis showed that the lncRNAs with high fold changes were correlated with many mRNAs, suggesting these may play key regulatory function in peri‐implantitis and periodontitis. For instance, the most down‐regulated lncRNA, DPP10‐antisense RNA‐1 (DPP‐10 AS‐1), is related to the DPP10 gene that is associated with increased IgE production by airway epithelial cells upon allergen stimulation . IgE is indicative of a Th2 type immune response and has been associated with titanium dioxide particles .…”