IL-4 activates ULK1/Atg9a/Rab9 in asthma, NLRP3 inflammasomes, and Golgi fragmentation by increasing autophagy flux and mitochondrial oxidative stress
Chang Xu,
Yilan Song,
Wanting Liu,
Ruobai Liu,
Qiaoyun Bai,
Liangchang Li,
Chongyang Wang,
Guanghai Yan
Affiliations
Chang Xu
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Yilan Song
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Wanting Liu
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Ruobai Liu
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Qiaoyun Bai
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Liangchang Li
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China
Chongyang Wang
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China; Corresponding author. Department of Anatomy, Histology and Embryology, Yanbian University Medical College, No. 977, Gongyuan Road, Yanji, 133002, PR China.
Guanghai Yan
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China; Corresponding author. Department of Anatomy, Histology and Embryology, Yanbian University Medical College, No. 977, Gongyuan Road, Yanji 133002, PR China.,
During asthma, there is an intensification of pulmonary epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. However, the underlying mechanism remains largely unknown. Therefore, this study investigated the roles of ULK1, Atg9a, and Rab9 in epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. We found that ULK1 gene knockout reduced the infiltration of inflammatory cells, restored the imbalance of the Th1/Th2 ratio, and inhibited the formation of inflammatory bodies in the lung tissue of house dust mite-induced asthma mice. Moreover, we demonstrated that Atg9a interacted with ULK1 at S467. ULK1 phosphorylated Atg9a at S14. Treatment with ULK1 activator (LYN-1604) and ULK1 inhibitor (ULK-101) respectively promoted and inhibited inflammasome activation, indicating that the activation of inflammasome induced by house dust mite in asthma mice is dependent on ULK1. For validation of the in vivo results, we then used a lentivirus containing ULK1 wild type and ULK1-S467A genes to infect Beas-2b-ULK1-knockout cells and establish a stable cell line. The results suggest that the ULK1 S467 site is crucial for IL-4-induced inflammation and oxidative stress. Experimental verification confirmed that Atg9a was the superior signaling pathway of Rab9. Interestingly, we found for the first time that Rab9 played a very important role in inflammation-induced fragmentation of the Golgi apparatus. Inhibiting the activation of the ULK1/Atg9a/Rab9 signaling pathways can inhibit Golgi apparatus fragmentation and mitochondrial oxidative stress in asthma while reducing the production of NLRP3-mediated pulmonary epithelial inflammation.
