Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal

Sonia Salzanoa, Paola Checconia, Eva-Maria Hanschmannc, Christopher Horst Lilligc, Lucas D. Bowlerd, Philippe Chane,f, David Vaudrye,f, Manuela Mengozzia, Lucia Coppoa, Sandra Sacrea, Kondala R. Atkurig, Bita Sahafg, Leonard A. Herzenbergg,Leonore A. Herzenbergg, Lisa Mullena, and Pietro Ghezzia.

Proceedings of the National Academy of Sciences 111, 12157-12162 (2014).

Speaker: Jyun-Cyuan Chang (張鈞筌)             Time: 13:00~14:00, Dec 17, 2014

Commentator: Dr. Chi-Chang Shieh (謝奇璋 老師)  Place: Room 601

Abstract:

The reactive oxygen species participate in most of diseases and cause oxidative stress which triggers protein oxidation and results in release of inflammation signal. [1]. The mechanism by which oxidative stress induces inflammation is unclear but is important. Glutathione (GSH) is the main intracellular thiol antioxidant that is found in oxidative stress. GSH could regulate immune response by forming disulfide bond between cysteine residue of protein and glutathione [2]. Peroxiredoxin-2 (PRDX2) is a redox-active enzyme that could be activated through disulfide dimerization. In this study, the authors found that glutathionylated PRDX2 were secreted by LPS-stimulated macrophage. The glutathionylated PRDX2 was also released during inflammation period both in vitro and in vivo. In inflammation cascade, the authors found that PRDX2 induced release of TNF-αand classified it as a danger signal which acts as an immune mediator. The Authors proved that PRDX2 is not only released by LPS-stimulated macrophage but also peripheral blood mononuclear cells (PBMC). Interestingly, unlike other inflammation cytokines, PRDX2 is constitutively presented in macrophages, and is released in oxidized form on LPS stimulation. Release of PRDX2 is not related to LPS-mediated induction of mRNA and protein synthesis. Importantly, the authors also showed that PRDX2 is released together with its substrate, thioredoxin 1 (TRX1). TRX1 could alter the redox state of membrane proteins and possibly change the structure of receptors on the membrane. Thereby, TRX1 can facilitate inflammation via cytokine and toll-like receptor. In conclusion, PRDX2 and TRX act as a danger signal released by inflammatory cells under stress. Many chronic inflammatory disease involves oxidative stress and cytokine activation, the pathway is worth exploring as a potential novel therapeutic.

References:

1. Freeman, B.A. & Crapo, J.D. Biology of disease: free radicals and tissue injury. Laboratory investigation; a journal of technical methods and pathology 47, 412-426 (1982).

2. McCord, J.M. Oxygen-derived free radicals in postischemic tissue injury. The New England journal of medicine 312, 159-163 (1985)