A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice
Fu-Chao Liu,
Huang-Ping Yu,
Po-Jen Chen,
Hsuan-Wu Yang,
Shih-Hsin Chang,
Cherng-Chyi Tzeng,
Wei-Jen Cheng,
You-Ren Chen,
Yeh-Long Chen,
Tsong-Long Hwang
Affiliations
Fu-Chao Liu
College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
Huang-Ping Yu
College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
Po-Jen Chen
Department of Cosmetic Science, Providence University, Taichung, 433, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan
Hsuan-Wu Yang
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan
Shih-Hsin Chang
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan
Cherng-Chyi Tzeng
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung, 807, Taiwan
Wei-Jen Cheng
Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Department of Traditional Chinese Medicine, Center of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
You-Ren Chen
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung, 807, Taiwan
Yeh-Long Chen
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung, 807, Taiwan; Corresponding author. Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Tsong-Long Hwang
Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, 243, Taiwan; Corresponding author. Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
Neutrophil infiltration plays a significant pathological role in inflammatory diseases. NADPH oxidase type 2 (NOX2) is a respiratory burst oxidase that generates large amounts of superoxide anion (O2•−) and subsequent other reactive oxygen species (ROS). NOX2 is an emerging therapeutic target for treating neutrophilic inflammatory diseases. Herein, we show that 4-[(4-(dimethylamino)butoxy)imino]-1-methyl-1H-benzo[f]indol-9(4H)-one (CYR5099) acts as a NOX2 inhibitor and exerts a protective effect against complete Freund's adjuvant (CFA)-induced inflammatory arthritis in mice. CYR5099 restricted the production of O2•− and ROS, but not the elastase release, in human neutrophils activated with various stimulators. The upstream signaling pathways of NOX2 were not inhibited by CYR5099. Significantly, CYR5099 inhibited NOX2 activity in activated human neutrophils and in reconstituted subcellular assays. In addition, CYR5099 reduced ROS production, neutrophil infiltration, and edema in CFA-induced arthritis in mice. Our findings suggest that CYR5099 is a NOX2 inhibitor and has therapeutic potential for treating neutrophil-dominant oxidative inflammatory disorders. Keywords: Inflammatory arthritis, CYR5099, NADPH oxidase 2, Neutrophil, Reactive oxygen species
