Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID‐exacerbated respiratory disease

Abstract

Background: Genetic variants of dipeptidyl peptidase 10 (DPP10) have been suggested to contribute to the development of NSAID-exacerbated respiratory disease (NERD). However, the mechanisms of how DPP10 contributes to NERD phenotypes remain unclear. Objective: To demonstrate the exact role of DPP10 in the pathogenesis of NERD. Methods: Patients with NERD (n = 110), those with aspirin-tolerant asthma (ATA, n = 130) and healthy control subjects (HCs, n = 80) were enrolled. Clinical characteristics were analysed according to the serum DPP10 levels in both NERD and ATA groups. The function of DPP10 in airway inflammation and remodelling was investigated with in vitro, ex vivo and in vivo experiments.Results: NERD patients had higher levels of serum DPP10 and TGF-β1 with lower FEV 1 than ATA patients or HCs (p < .05 for each). NERD patients with higher DPP10 levels had higher TGF-β1, but lower FEV 1 (p < .05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10 levels had a positive correlation with TGF-β1 (r = 0.384, p < .001), but a negative correlation with FEV 1 (r = −0.230, p = .016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-β1 treatments. Furthermore, DPP10 was found to be produced from immune cells and this molecule induced the ERK phosphorylation in airway epithelial cells, which was suppressed by anti-DPP10 treatment. In asthmatic mouse models, increased levels of DPP10 in the serum and TGF-β1 in the bronchoalveolar lavage fluid were noted, which were suppressed by anti-DPP10 treatment. Moreover, anti-DPP10 treatment inhibited the ERK phosphorylation and extracellular matrix deposition in the lungs. Conclusions and ClinicalRelevance: These findings suggest that increased production of DPP10 may contribute to TGF-β1-mediated airway dysfunction in NERD patients, where blockade of DPP10 may have potential benefits.

Emerging Biomarkers Beyond Leukotrienes for the Management of Nonsteroidal Anti-inflammatory Drug (NSAID)-Exacerbated Respiratory Disease

“…Dipeptidyl peptidase 10 (DPP10) expressed in the airway epithelium is associated with asthma and lung function decline. 65 66 Higher serum DPP10 levels negatively correlated with FEV1% in patients with NERD than in those with ATA ( Table ). Furthermore, a positive correlation was observed between serum levels of DPP10 and TGF-β1 in patients with NERD.…”

“…Furthermore, a positive correlation was observed between serum levels of DPP10 and TGF-β1 in patients with NERD. 65 A genome-wide association study (GWAS) demonstrated the significant association of a single nucleotide polymorphism in DPP10 with NERD. 66 67 These findings have suggested that DPP10 could contribute to the decline in the lung function in NERD.…”

Biomarkers of immediate drug hypersensitivity

“…Serum levels of TGF‐β1 were significantly higher in NERD patients than in ATA and positively correlated with urinary LTE4 levels 101 . Moreover, serum levels of dipeptidyl peptidase 10 (DDP10) may be also a potential biomarker to distinguish NERD from ATA and predict disease severity as a positive correlation has been found with TGF‐β1 in patients with NERD 102 …”

“…101 Moreover, serum levels of dipeptidyl peptidase 10 (DDP10) may be also a potential biomarker to distinguish NERD from ATA and predict disease severity as a positive correlation has been found with TGF-β1 in patients with NERD. 102 Surfactant protein D (SPD) interacts with phagocytic cells attenuating airway inflammation and remodelling. Therefore, serum SPD levels were lower and negatively correlated with FEV1% decrease after aspirin challenges in patients with NERD than with ATA.…”

Immunologic Basis of Type 2 Biologics for Severe Asthma

“…In addition to mediators related to immune cells, epithelium-derived cytokines, including IL-25, IL-33, and TSLP, which subsequently induce activation of group 2 innate lymphoid cells (ILC2s), have been emphasized in SA with persistent eosinophilic airway inflammation ( 18 ). Furthermore, close interplays between airway epithelial cells (AECs) and immune cells (increased levels of folliculin and dipeptidyl peptidase 10, but decreased levels of surfactant protein D) could induce airway inflammation, and remodeling has been demonstrated in patients with aspirin-exacerbated respiratory disease (AERD), a phenotype of SA ( 19 20 21 22 23 24 25 ). Although many molecules have been highlighted in type 2 asthma related to disease severity, recent biologics under clinical trials mainly focus on targeting IL-4, IL-5, IL-33, and TSLP.…”