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

doi:10.1016/j.redox.2019.101273

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English
Article number	101273
Journal	Redox Biology
Volume	26
DOIs	https://doi.org/10.1016/j.redox.2019.101273
State	Published - 09 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

CYR5099
Inflammatory arthritis
NADPH oxidase 2
Neutrophil
Reactive oxygen species

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.redox.2019.101273

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title = "A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice",

abstract = "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.",

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author = "Liu, {Fu Chao} and Yu, {Huang Ping} and Chen, {Po Jen} and Yang, {Hsuan Wu} and Chang, {Shih Hsin} and Tzeng, {Cherng Chyi} and Cheng, {Wei Jen} and Chen, {You Ren} and Chen, {Yeh Long} and Hwang, {Tsong Long}",

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AU - Yu, Huang Ping

AU - Chen, Po Jen

AU - Yang, Hsuan Wu

AU - Chang, Shih Hsin

AU - Tzeng, Cherng Chyi

AU - Cheng, Wei Jen

AU - Chen, You Ren

AU - Chen, Yeh Long

AU - Hwang, Tsong Long

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AB - 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.

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KW - Inflammatory arthritis

KW - NADPH oxidase 2

KW - Neutrophil

KW - Reactive oxygen species

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A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice

Abstract

Bibliographical note

Keywords

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