Targeting inflammation-immune response as a novel strategy for the treatment of brain infarction

• Project/Area Number: 23591262
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Fukuoka Dental College
• Principal Investigator: OOBOSHI Hiroaki 福岡歯科大学, 歯学部, 教授 (10311838)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 脳梗塞 / TLR / DAMPs / Peroxiredoxin / マクロファージ / インターロイキン23 / インターロイキン17 / γδT細胞 / peroxiredoxin / 脳虚血 / 炎症 / 自然免疫 / 遺伝子治療 / 免疫 / 遺伝子導入 / T細胞 / インターロイキン

Research Abstract

Immune responses following stroke continue to be an active area of investigation. Prior work has shown that lymphocytes lead to worsened outcome. However, the role of T lymphocyte subtypes has not been well studied. We have recently reported that the gamma-deltaT cells can produce IL-17 following stimulation by macrophage derived IL-23. These cytokines appear to contribute negatively to stroke evolution, as mice deficient in these cytokines are protected. In this study, peroxiredoxin (Prx), an endogenous antioxidant, was identified as a danger signal. Prx is shown to induce IL-23 and leads to worsened stroke outcome through toll-like receptors-2 and -4 pathway. These findings show that Prx is a novel damage-associated molecular patterns (DAMPs) and inhibiting Prx appears to be protective.

Research Products

• [Journal Article] Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia (2014)
  • Author(s): Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T
  • Journal Title: Am J Physiol Renal Physiol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Plasma S100A12 is associated with functional outcome after ischemic stroke : Research for Biomarkers in Ischemic Stroke (2014)
  • Author(s): Wakisaka Y, Ago T, Kamouchi M, Kuroda J, Matsuo R, Hata J, Gotoh S, Isomura T, Awano H, Suzuki K, Fukuda K, Okada Y, Kiyohara Y, Ooboshi H, Kitazono T; REBIOS Investigators
  • Journal Title: J Neurol Sci Volume: 340 Pages: 75-9
  • Peer Reviewed
• [Journal Article] ABCD3 and ABCD3-I scores are superior to ABCD2 score in the prediction of short- and long-term risks of stroke after transient ischemic attack (2014)
  • Author(s): Kiyohara T, Kamouchi M, Kumai Y, Ninomiya T, Hata J, Yoshimura S, Ago T, Okada Y, Kitazono T; Fukuoka Stroke Registry Investigators (Ooboshi H)
  • Journal Title: Stroke Volume: 45 Pages: 418-25
  • Peer Reviewed
• [Journal Article] High blood pressure after acute ischemic stroke is associated with poor clinical outcomes : Fukuoka Stroke Registry (2014)
  • Author(s): Ishitsuka K, Kamouchi M, Hata J, Fukuda K, Matsuo R, Kuroda J, Ago T, Kuwashiro T, Sugimori H, Nakane H, Kitazono T; FSR Investigators (Ooboshi H)
  • Journal Title: Hypertension Volume: 63 Pages: 54-60
  • Peer Reviewed
• [Journal Article] High blood pressure after acute ischemic stroke is associated with poor clinical outcomes: Fukuoka Stroke Registry. (2014)
  • Author(s): Ishitsuka K, Kamouchi M, Hata J, Fukuda K, Matsuo R, Kuroda J, Ago T, Kuwashiro T, Sugimori H, Nakane H, Kitazono T; FSR Investigators (Ooboshi H)
  • Journal Title: Hypertension Volume: 63 Issue: 1 Pages: 54-60
  • DOI: 10.1161/hypertensionaha.113.02189
  • Peer Reviewed
• [Journal Article] ABCD3 and ABCD3-I scores are superior to ABCD2 score in the prediction of short- and long-term risks of stroke after transient ischemic attack. (2014)
  • Author(s): Kiyohara T, Kamouchi M, Kumai Y, Ninomiya T, Hata J, Yoshimura S, Ago T, Okada Y, Kitazono T; Fukuoka Stroke Registry Investigators (Ooboshi H).
  • Journal Title: Stroke Volume: 45 Issue: 2 Pages: 418-25
  • DOI: 10.1161/strokeaha.113.003077
  • Peer Reviewed / Open Access
• [Journal Article] Plasma S100A12 is associated with functional outcome after ischemic stroke: Research for Biomarkers in Ischemic Stroke. (2014)
  • Author(s): Wakisaka Y, Ago T, Kamouchi M, Kuroda J, Matsuo R, Hata J, Gotoh S, Isomura T, Awano H, Suzuki K, Fukuda K, Okada Y, Kiyohara Y, Ooboshi H, Kitazono T; REBIOS Investigators.
  • Journal Title: J Neurol Sci Volume: 340 Issue: 1-2 Pages: 75-9
  • DOI: 10.1016/j.jns.2014.02.031
  • Peer Reviewed
• [Journal Article] Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. (2014)
  • Author(s): Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T
  • Journal Title: Am J Physiol Renal Physiol Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Neuroprotection after cerebral ischemia (2013)
  • Author(s): Namura S, Ooboshi H, Liu J, Yenari MA
  • Journal Title: Ann N Y Acad Sci Volume: 1278 Pages: 25-32
  • Peer Reviewed
• [Journal Article] IT network establishment for neuropatients (2013)
  • Author(s): Abe K, Uchiyama S, Matsubara E, Muramatsu S, Atsuta N, Kitagawa K, Iguchi Y, Ooboshi H, Kaji R, Terao Y
  • Journal Title: Rinsho Shinkeigaku Volume: 53 Pages: 1155-8
  • NAID: 130004505370
  • Peer Reviewed
• [Journal Article] Slowly progressive and painless thoracic aortic dissection presenting with a persistent Fever in an elderly patient: the usefulness of combined measurement of biochemical parameters. (2013)
  • Author(s): Yamada S, Tokumoto M, Ohkuma T, Kansui Y, Wakisaka Y, Uchizono Y, Tsuruya K, Kitazono T, Ooboshi H.
  • Journal Title: Case Rep Med Volume: 2013 Pages: 498129-498129
  • DOI: 10.1155/2013/498129
  • Peer Reviewed
• [Journal Article] IT network establishment for neuropatients. (2013)
  • Author(s): Abe K, Uchiyama S, Matsubara E, Muramatsu S, Atsuta N, Kitagawa K, Iguchi Y, Ooboshi H, Kaji R, Terao Y
  • Journal Title: Rinsho Shinkeigaku Volume: 53 Pages: 1158-8
  • NAID: 130004505370
  • Peer Reviewed
• [Journal Article] Neuroprotection after cerebral ischemia. (2013)
  • Author(s): Namura S, Ooboshi H, Liu J, Yenari MA.
  • Journal Title: Ann N Y Acad Sci Volume: 1278(1) Issue: 1 Pages: 25-32
  • DOI: 10.1111/nyas.12087
  • Peer Reviewed
• [Journal Article] Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke (2012)
  • Author(s): Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H
  • Journal Title: J Neurochem Volume: 123S2 Pages: 29-38
  • Peer Reviewed
• [Journal Article] Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain (2012)
  • Author(s): Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A
  • Journal Title: Nat Med Volume: 18 Pages: 911-7
  • Peer Reviewed
• [Journal Article] PDGF receptor ß signaling in pericytes following ischemic brain injury (2012)
  • Author(s): Arimura K, Ago T, Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, Sugimori H, Ooboshi H, Sasaki T, Kitazono T
  • Journal Title: Curr Neurovasc Res Volume: 9 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Risk factors predisposing to stroke recurrence within one year of non-cardioembolic stroke onset : the Fukuoka Stroke Registry (2012)
  • Author(s): Kuwashiro T, Sugimori H, Ago T, Kamouchi M, Kitazono T; FSR Investigators (Ooboshi H)
  • Journal Title: Cerebrovasc Dis Volume: 33 Pages: 141-9
  • Peer Reviewed
• [Journal Article] Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. (2012)
  • Author(s): Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H.
  • Journal Title: J Neurochem Volume: 123(S2) Pages: 29-38
  • Peer Reviewed
• [Journal Article] Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain (2012)
  • Author(s): Shichita T
  • Journal Title: Nature Medicine Volume: 18 Issue: 6 Pages: 911-917
  • DOI: 10.1038/nm.2749
  • Peer Reviewed
• [Journal Article] PDGF receptor ß signaling in pericytes following ischemic brain injury. (2012)
  • Author(s): Arimura K, Ago T, Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, Sugimori H, Ooboshi H, Sasaki T, Kitazono T
  • Journal Title: Curr Neurovasc Res Volume: 9 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Risk factors predisposing to stroke recurrence within one year of non-cardioembolic stroke onset: the Fukuoka Stroke Registry. (2012)
  • Author(s): Kuwashiro T, Sugimori H, Ago T, Kamouchi M, Kitazono T; FSR Investigators.
  • Journal Title: Cerebrovasc Dis Volume: 33 Pages: 141-149
  • Peer Reviewed
• [Journal Article] Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke : the Fukuoka Stroke Registry (2011)
  • Author(s): Kamouchi M, Matsuki T, Hata J, Kuwashiro T, Ago T, Sambongi Y, Fukushima Y, Sugimori H, Kitazono T; FSR Investigators (Ooboshi H)
  • Journal Title: Stroke Volume: 42 Pages: 2788-94
  • Peer Reviewed
• [Journal Article] Gene therapy as a novel pharmaceutical intervention for stroke (2011)
  • Author(s): Ooboshi H
  • Journal Title: Curr Pharm Des Volume: 17 Pages: 424-33
  • Peer Reviewed
• [Journal Article] Gene therapy as a novel pharmaceutical intervention for stroke. (2011)
  • Author(s): Ooboshi H
  • Journal Title: Curr Pharm Des Volume: 17 Pages: 424-433
  • Peer Reviewed
• [Journal Article] Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka Stroke Registry. (2011)
  • Author(s): Kamouchi M, Matsuki T, Hata J, Kuwashiro T, Ago T, Sambongi Y, Fukushima Y, Sugimori H, Kitazono T; FSR Investigators.
  • Journal Title: Stroke Volume: 42 Pages: 2788-2794
  • Peer Reviewed
• [Presentation] Basic fibroblast growth factor after ischemic stroke in diabetic patients - Research for Biomarkers in Ischemic Stroke (REBIOS) - (2014)
  • Author(s): Nakamura K, Ago T, Arimura K, Makihara N, Nishimura A, Matsuo R, Kuroda J, Wakisaka Y, Isomura T, Awano H, Suzuki K, Okada Y, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T
  • Organizer: International Stroke Conference 2014
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-02-12
• [Presentation] Basic fibroblast growth factor after ischemic stroke in diabetic patients - Research for Biomarkers in Ischemic Stroke (REBIOS) -. (2014)
  • Author(s): Nakamura K, Ago T, Arimura K, Makihara N, Nishimura A, Matsuo R, Kuroda J, Wakisaka Y, Isomura T, Awano H, Suzuki K, Okada Y, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T
  • Organizer: International Stroke Conference 2014
  • Place of Presentation: San Diego, USA
• [Presentation] The expression of pericyte PDGFRβis regulated by basic FGF after ischemic stroke - Research for Biomarkers in Ischemic Stroke (REBIOS) - (2013)
  • Author(s): Nakamura K, Arimura K, Ago T, Makihara N, Isomura T, Watabe W, Awano H, Suzuki K, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T
  • Organizer: Neuroscience Meeting 2013
  • Place of Presentation: San Diego, USA
  • Year and Date: 2013-11-09
• [Presentation] Phosphate overload induces systemic inflammation, malnutrition, and vascular calcification in uremia (2013)
  • Author(s): Yamada S, Tokumoto M, Taniguchi M, Tsuruya K, Ooboshi H, and Kitazono T
  • Organizer: ASN Kidney Week 2013
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2013-11-08
• [Presentation] The combined therapy with calcitriol and a calcimimetic agent, R568, ameliorates phosphorus-induced calcification with altered expression of SIRT1 and ALP in human vascular smooth muscle cells (2013)
  • Author(s): Tokumoto M, Yamada S, Fujino T, Tsuruya K, Kitazono T, Ooboshi H
  • Organizer: ASN Kidney Week 2013
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2013-11-08
• [Presentation] 脳梗塞発症後の糖尿病患者におけるbasic FGFの上昇: Research for Biomarkers in Ischemic Stroke (REBIOS) (2013)
  • Author(s): 中村晋之、吾郷哲朗、有村公一、牧原典子、粟野秀人、鈴木一夫、清原裕、鴨打正浩、大星博明、北園孝成
  • Organizer: 日本脳循環代謝学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-11-01
• [Presentation] 脳梗塞後のS100A12血漿濃度は昨日予後不良と挿管する:Research for Biomarkers in Ischemic Stroke (2013)
  • Author(s): 脇坂義信,吾郷哲朗,鴨打正浩,磯村哲,粟野秀人,鈴木一夫,岡田靖,清原裕,大星博明,北園孝成
  • Organizer: 第38回日本脳卒中学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-21
• [Presentation] Extracellular newly identified receptor for advanced glycation endproducts binding protein (EN-RAGE) predicts the outcome in patients with acute ischemic stroke : Research for Biomarkers in Ischemic Stroke (2013)
  • Author(s): Wakisaka Y, Ago T, Kamouchi M, Kuroda J, Matsuo R, Gotoh S, Watanabe W, Isomura T, Awano H, Suzuki K, Fukuda K, Okada Y, Kiyohara Y, Ooboshi H, Kitazono T
  • Organizer: International Stroke Conference 2013
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2013-02-06
• [Presentation] The expression of pericyte PDGFRβ is regulated by basic FGF after ischemic stroke - Research for Biomarkers in Ischemic Stroke (REBIOS) -. (2013)
  • Author(s): Nakamura K, Arimura K, Ago T, Makihara N, Isomura T, Watabe W, Awano H, Suzuki K, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] Phosphate overload induces systemic inflammation, malnutrition, and vascular calcification in uremia. (2013)
  • Author(s): Yamada S, Tokumoto M, Taniguchi M, Tsuruya K, Ooboshi H, and Kitazono T
  • Organizer: ASN Kidney Week 2013
  • Place of Presentation: Atlanta, USA
• [Presentation] The combined therapy with calcitriol and a calcimimetic agent, R568, ameliorates phosphorus-induced calcification with altered expression of SIRT1 and ALP in human vascular smooth muscle cells. (2013)
  • Author(s): Tokumoto M, Yamada S, Fujino T, Tsuruya K, Kitazono T, Ooboshi H
  • Organizer: ASN Kidney Week 2013
  • Place of Presentation: Atlanta, USA
• [Presentation] 脳梗塞後のS100A12血漿濃度は昨日予後不良と挿管する：Research for Biomarkers in Ischemic Stroke (2013)
  • Author(s): 脇坂義信, 吾郷哲朗, 鴨打正浩, 磯村哲, 粟野秀人, 鈴木一夫, 岡田靖, 清原裕, 大星博明, 北園孝成
  • Organizer: 第38回日本脳卒中学会総会
  • Place of Presentation: 東京
• [Presentation] Extracellular newly identified receptor for advanced glycation endproducts binding protein (EN-RAGE) predicts the outcome in patients with acute ischemic stroke: Research for Biomarkers in Ischemic Stroke (2013)
  • Author(s): Wakisaka Y, Ago T, Kamouchi M, Kuroda J, Matsuo R, Gotoh S, Watanabe W, Isomura T, Awano H, Suzuki K, Fukuda K, Okada Y, Kiyohara Y, Ooboshi H, Takanari K
  • Organizer: Stroke 2013
  • Place of Presentation: Honolulu
• [Presentation] Innate immunity as a novel therapeutic target of brain infarction (2012)
  • Author(s): Hiroaki Ooboshi
  • Organizer: Transpacific Workshop o Stroke
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-18
• [Presentation] Immune response as a novel therapeutic target of brain infarction (2012)
  • Author(s): 大星博明
  • Organizer: 第44回日本動脈硬化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-07-19
• [Presentation] Innate immunity as a novel therapeutic target of brain infarction. (2012)
  • Author(s): Hiroaki Ooboshi
  • Organizer: Transpacific Workshop o Stroke
  • Place of Presentation: New Orleans
  • Invited
• [Presentation] Immune response as a novel therapeutic target of brain infarction. (2012)
  • Author(s): 大星博明
  • Organizer: 第44回日本動脈硬化学会総会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] T細胞と脳虚血後炎症 (2011)
  • Author(s): 七田崇、大星博明、北園孝成、石井哲郎、黒田和道、三宅健介、審良静男、吉村昭彦
  • Organizer: 第23回日本脳循環代謝学会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-05
• [Presentation] Innate immune response as a novel therapeutic target of brain infarction (2011)
  • Author(s): Ooboshi H
  • Organizer: First Turkish International Stroke Meeting
  • Place of Presentation: Antalya, Turkey
  • Year and Date: 2011-10-02
• [Presentation] IL-23 production from infiltrating macrophage in the ischemic brain is dependent on TLR signaling pathway (2011)
  • Author(s): Shichita T, Ooboshi H, Takada I, Ishii T, Kuroda K, Miyake K, Yoshimura A
  • Organizer: XXVth International Symposium on Cerebral Blood Flow and Metabolism (Brain 2011)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2011-05-27
• [Presentation] Innate immune response as a novel therapeutic target of brain infarction. (2011)
  • Author(s): Ooboshi H
  • Organizer: The First International Turkish Stroke Meeting(招待講演)
  • Place of Presentation: トルコ共和国、Antalya
• [Presentation] IL-23 production from infiltrating macrophage in the ischemic brain is dependent on TLR signaling pathway. (2011)
  • Author(s): Shichita T, Ooboshi H, Takada I, Ishii T, Kuroda K, Miyake K, Yoshimura A
  • Organizer: 第25回国際脳循環代謝学会
  • Place of Presentation: スペイン、Barcelona
• [Presentation] T細胞と脳虚血後炎症 (2011)
  • Author(s): 七田崇、大星博明、北園孝成、石井哲郎、黒田和道、三宅健介、審良静男、吉村昭彦
  • Organizer: 第23回日本脳循環代謝学会(招待講演)
  • Place of Presentation: 東京
• [Book] 無症候性脳出血とmicrobleeds.脳血管障害の治療最前線 (2014)
  • Author(s): 大星博明
  • Publisher: 中山書店
• [Book] Midkine gene transfer in brain infarction. Chap 13, Midkine : From Embryogenesis to Pathogenesis and Therapy (2012)
  • Author(s): Ooboshi H, Ishikawa E, Takada J, Shichita T, Kumai Y
  • Total Pages: 38
  • Publisher: Springer Science
• [Book] Midkine gene transfer in brain infarction. Ch 13, Midkine: From Embryogenesis to Pathogenesis and Therapy (2012)
  • Author(s): Ooboshi H, Ishikawa E, Takada J, Shichita T, Kumai Y.
  • Total Pages: 380
  • Publisher: Springer Science
• [Book] Midkine: From Embryogenesis to Pathogenesis and Therapy, in press Springer Science (2012)
  • Author(s): Ooboshi H, Ishikawa E, Takada J, Shichita T, Kumai Y
  • Total Pages: 380
  • Publisher: Springer Science