Pivotal role of cerebral interleukin-17-producing T cells in the delayed phase of ischemic brain injury

Takashi Shichita, Yuki Sugiyama, Hiroaki Ooboshi, Hiroshi Sugimori, Ryusuke Nakagawa, Ichiro Takada, Toru Iwaki, Yasunori Okada, Mitsuo Iida, Daniel J. Cua, Yoichiro Iwakura, Akihiko Yoshimura

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511 Citations (Scopus)

Abstract

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that T lymphocytes, but not CD4 + helper T cells, were a major source of IL-17. Moreover, depletion of T lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including T lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

Original languageEnglish
Pages (from-to)946-950
Number of pages5
JournalNature medicine
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 1 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., Iwaki, T., Okada, Y., Iida, M., Cua, D. J., Iwakura, Y., & Yoshimura, A. (2009). Pivotal role of cerebral interleukin-17-producing T cells in the delayed phase of ischemic brain injury. Nature medicine, 15(8), 946-950. https://doi.org/10.1038/nm.1999