Abstract
Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.
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Acknowledgements
We thank N. Saito, N. Shiino and M. Asakawa for technical assistance. This work was supported by special grants-in-aid (A) and open research for young academics and specialists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, PRESTO and CREST from the Japan Science and Technology Agency, an Intramural Research Grant (22-4) for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry (NCNP), the SENSHIN Research Foundation, the Takeda Science Foundation, the Uehara Memorial Foundation, the Mochida Memorial Foundation, the Scientific Research Fund from the Ministry of Health, Labor and Welfare of Japan (09156274) and the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation.
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T. Shichita designed and performed experiments, analyzed data and wrote the manuscript; E.H. and A.K. performed TLR-deficient mouse analysis; R.M., R.S. and T. Sekiya participated in data analysis and discussion; I.T. provided specific input on protein analysis; H.O. and T.K. provided technical advice about experimental design; T.Y. and T.I. provided crucial input on Prx1's functions; H.T., S.M. and M.N. provided the HMGB1-specific antibody and crucial input on HMGB1; K.K. provided specific input regarding LC-MS analysis; K.M. and S.A. provided TLR2 and/or TLR4-deficient mice; A.Y. initiated and directed the entire study, designed experiments and wrote the manuscript.
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Shichita, T., Hasegawa, E., Kimura, A. et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18, 911–917 (2012). https://doi.org/10.1038/nm.2749
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DOI: https://doi.org/10.1038/nm.2749
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