Redox regulation of pro-IL-1β processing may contribute to the increased severity of serum-induced arthritis in NOX2-deficient mice

Ya Fang Huang, Pei Chi Lo, Chia Liang Yen, Peter Andrija Nigrovic, Wen Chen Chao, Wei Zhi Wang, George Chengkang Hsu, Yau Sheng Tsai, Chi Chang Shieh

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7 Citations (Scopus)

Abstract

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/p47phox 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.

Original languageEnglish
Pages (from-to)973-984
Number of pages12
JournalAntioxidants and Redox Signaling
Volume23
Issue number12
DOIs
Publication statusPublished - 2015 Oct 20

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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