Effect of TGF-β1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease

• Published in: PloS one 2021-08, Vol.16 (8), p.e0256237-e0256237
• Main Authors: Choi, Youngwoo, Sim, Soyoon, Lee, Dong-Hyun, Lee, Hee-Ra, Ban, Ga-Young, Shin, Yoo Seob, Kim, Yoon-Keun, Park, Hae-Sim
• Format: Article
• Language: English
• Subjects: Adult; Airway management; Animals; Aspirin; Aspirin - adverse effects; Aspirin - therapeutic use; Asthma; Asthma, Aspirin-Induced - blood; Asthma, Aspirin-Induced - genetics; Asthma, Aspirin-Induced - pathology; Biology and Life Sciences; Cell activation; Degranulation; Eosinophilia; Eosinophils; Eosinophils - metabolism; Eosinophils - pathology; Female; Gene Expression Regulation - drug effects; Glutathione Transferase - urine; Growth factors; Humans; Immunology; Inflammation; Inflammation - blood; Inflammation - chemically induced; Inflammation - genetics; Inflammation - pathology; Leukocytes (eosinophilic); Leukotriene E4 - biosynthesis; Leukotriene E4 - blood; Leukotriene E4 - genetics; Leukotriene-C4 synthase; Male; Medicine; Medicine and Health Sciences; Mice; Middle Aged; p38 Mitogen-Activated Protein Kinases - genetics; Pathogenesis; Patients; Proteins; Receptors, Leukotriene - metabolism; Respiratory diseases; Respiratory System - drug effects; Respiratory System - metabolism; Respiratory System - pathology; Respiratory System Abnormalities - blood; Respiratory System Abnormalities - chemically induced; Respiratory System Abnormalities - genetics; Respiratory System Abnormalities - pathology; Respiratory tract diseases; Transforming Growth Factor beta1 - blood; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0256237

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.