Nrf2 Deficiency Accelerates IL-17-Dependent Neutrophilic Airway Inflammation in Asthmatic Mice

• Published in: Antioxidants Vol. 13; no. 7; p. 818
• Main Authors: Kuramoto, Kenya, Morishima, Yuko, Yoshida, Kazufumi, Ano, Satoshi, Kawashima, Kai, Yabuuchi, Yuki, Sakai, Chio, Matsumura, Sosuke, Nishino, Kengo, Yazaki, Kai, Matsuyama, Masashi, Kiwamoto, Takumi, Ishii, Yukio, Hizawa, Nobuyuki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.07.2024
• Subjects: Animal models; Antigens; Antioxidants; Asthma; Cell differentiation; Cytokines; GATA-3 protein; Genes; Helper cells; IL-17; Inflammation; Laboratories; Lavage; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lungs; Lymphocytes T; Monoclonal antibodies; neutrophilic inflammation; Neutrophils; Nrf2; Oxidative stress; Pathogens; Respiratory system; Respiratory tract diseases; RORγt; Smoking; Steroids; Th17; Tumor necrosis factor-TNF; United States > US; Japan; neutrophilic inflammation; asthma; Nrf2; Th17; IL-17; RORγt
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox13070818

Asthma is a heterogeneous disease that can be broadly classified into type 2, which is primarily steroid-sensitive and eosinophilic, and non-type 2, which is primarily steroid-resistant and neutrophilic. While the mechanisms leading to the development of molecular-targeted therapies for type 2 asthma are being elucidated, much remains to be learned about non-type 2 asthma. To investigate the role of oxidative stress in refractory allergic airway inflammation, we compared asthma models generated by immunizing wild-type and nuclear factor erythroid-2-related factor 2 (Nrf2)-deficient mice with the house dust mite antigen. Both asthma models had similar levels of airway inflammation and hyperresponsiveness, but the Nrf2-deficient mice had increased oxidative stress and exacerbated neutrophilic airway inflammation compared with the wild-type mice. Type 2 cytokines and the expression of GATA3, a transcription factor that is important for Th2 cell differentiation, had decreased in Nrf2-deficient mice compared with the wild-type mice, whereas helper T (Th) 17 cytokines and the expression of RORγt, which is important for Th17 cell differentiation, had increased. Furthermore, the neutrophilic airway inflammation caused by Nrf2 deficiency was ameliorated by interleukin (IL)-17 neutralization. We have concluded that the disruption of the Nrf2-mediated antioxidant defense system contributed to the induction of Th17 differentiation and exacerbated allergic neutrophilic airway inflammation.