title: Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma.
abstract: In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Yang
authors.affiliation: The First Clinic College, Chongqing Medical University, Chongqing 401331, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Dai
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Niu
authors.affiliation: First Department of Respiratory Disease, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Xiefang
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
authors.forename: Anjie
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; State Key Laboratories of Respiratory Disease, Ghuangzhou Medical University, Guangdong 510120, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratories of Respiratory Disease, Ghuangzhou Medical University, Guangdong 510120, China. Electronic address: Nanshan@vip.163.com.
authors.forename: Nanshan
authors.initials: N
authors.lastname: Zhong
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 N Columbia Rd, Grand Forks, ND 58203-9037, United States. Electronic address: min.wu@med.und.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; First Department of Respiratory Disease, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China. Electronic address: lzlgp@163.com.
authors.forename: Guoping
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism*; D015415:Biomarkers; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D055271:Mucin 5AC / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018793:Interleukin-13; D055271:Mucin 5AC; D016328:NF-kappa B; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Asthma; Endoplasmic reticulum stress; Lyn kinase; MUC5AC; Mucus secretion