Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain

Nature Medicine volume 18, pages911–917(2012)Cite this article

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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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Figure 1: Peroxiredoxins in brain lysate are potent inducers of IL-23 expression.
Figure 2: Extracellular peroxiredoxin colocalizes with infiltrating macrophages in the ischemic brain.
Figure 3: Peroxiredoxins induce IL-23 expression via TLR2 and TLR4.
Figure 4: Extracellular release of Prxs contributes to the initiation of post-ischemic inflammation.
Figure 5: Neutralization of extracellular Prxs is neuroprotective within 12 h after stroke onset.
Figure 6: The conserved region of peroxiredoxins was essential for IL-23-inducing activity and the increase in infarct size.

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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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Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan

    Takashi Shichita, Eiichi Hasegawa, Akihiro Kimura, Rimpei Morita, Ryota Sakaguchi, Ichiro Takada, Takashi Sekiya & Akihiko Yoshimura

  2. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan

    Takashi Shichita

  3. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Takashi Shichita & Takanari Kitazono

  4. Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan

    Hiroaki Ooboshi

  5. Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Toru Yanagawa & Tetsuro Ishii

  6. Department of Pharmacology, Okayama University Graduate School of Medicine, Okayama, Japan

    Hideo Takahashi, Shuji Mori & Masahiro Nishibori

  7. Division of Microbiology, Nihon University School of Medicine, Tokyo, Japan

    Kazumichi Kuroda

  8. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Shizuo Akira

  9. Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Kensuke Miyake

  10. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan

    Akihiko Yoshimura

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  1. Takashi Shichita
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Contributions

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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Correspondence to Akihiko Yoshimura.

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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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