Journal
REDOX BIOLOGY
Volume 26, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2019.101273
Keywords
Inflammatory arthritis; CYR5099; NADPH oxidase 2; Neutrophil; Reactive oxygen species
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 108-2320-B-126-001, MOST 106-2320-B-255-003-MY3, MOST 104-2320-B-255-004-MY3, MOST 105-2314-B-182A-012-MY3, MOST 107-2320-B-037-013, MOST 105-2314-B-182A-137-MY3]
- Ministry of Education, Taiwan [EMRPD1I0441, EMRPD1I0501]
- Chang Gung Memorial Hospital, Taiwan [CMRPG3H0811, CMRPF1F0061similar to3, CMRPF1G0241similar to3, CMRPG3E1552, CMRPG3G1601, CMRPG3F6221similar to3, BMRP450]
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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 (O-2(center dot-)) 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 O-2(center dot-) 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.
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