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Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice

Aims: To elucidate the role of reactive oxygen species (ROS) in arthritis and to identify targets of arthritis treatment in conditions with different levels of oxidant stress. Results: Through establishing an arthritis model by injecting arthritogenic serum into wild-type and NADPH oxidase 2 (NOX2)-...

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Detalles Bibliográficos
Autores principales: Huang, Ya-Fang, Lo, Pei-Chi, Yen, Chia-Liang, Nigrovic, Peter Andrija, Chao, Wen-Chen, Wang, Wei-Zhi, Hsu, George Chengkang, Tsai, Yau-Sheng, Shieh, Chi-Chang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624247/
https://www.ncbi.nlm.nih.gov/pubmed/25867281
http://dx.doi.org/10.1089/ars.2014.6136
Descripción
Sumario:Aims: To elucidate the role of reactive oxygen species (ROS) in arthritis and to identify targets of arthritis treatment in conditions with different levels of oxidant stress. Results: Through establishing an arthritis model by injecting arthritogenic serum into wild-type and NADPH oxidase 2 (NOX2)-deficient mice, we found that arthritis had a neutrophilic infiltrate and was more severe in Ncf1(−/−) mice, a mouse strain lacking the expression of the NCF1/p47(phox) component of NOX2. The levels of interleukin-1β (IL-1β) and IL-6 in inflamed joints were higher in Ncf1(−/−) than in controls. Antagonists of tumor necrosis factor-α (TNFα) and IL-1β were equally effective in suppressing arthritis in wild-type mice, while IL-1β blockade was more effective than TNFα blockade in Ncf1(−/−) mice. A treatment of caspase inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a cathepsin inhibitor alone, suppressed arthritic severity in the wild-type mice, while a treatment of cathepsin inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a caspase inhibitor alone, were effective in treating Ncf1(−/−) mice. Consistently, cathepsin B was found to proteolytically process pro-IL-1β to its active form and this activity was suppressed by ROS. Innovation: This novel mechanism of a redox-mediated immune regulation of arthritis through leukocyte-produced ROS is important for devising an optimal treatment for patients with different levels of tissue ROS. Conclusion: Our results suggest that ROS act as a negative feedback to constrain IL-1β-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2. Antioxid. Redox Signal. 23, 973–984.