Activation of M2-type macrophages in the late phase of cerebral ischemia promotes neurogenesis with cleaning of the infarct area.

• Project/Area Number: 15K10306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Fukuoka University (2016-2017); The University of Tokushima (2015)
• Principal Investigator: Yagi Kenji 福岡大学, 医学部, 講師 (80551837)
• Co-Investigator(Kenkyū-buntansha): 宇都 義浩 徳島大学, 大学院社会産業理工学研究部(生物資源産業学域), 教授 (20304553) ; 永廣 信治 徳島大学, 病院, 病院長 (60145315)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脳・神経 / 脳梗塞 / Ｍ１/Ｍ２様マクロファージ / 炎症性サイトカイン / phagocytosis / 神経再生 / Ｍ１/Ｍ２マクロファージ / 炎症性ｻｲﾄｶｲﾝ

Outline of Final Research Achievements

Brain ischemia promotes the recruitment of various cell types to the brain. Group-specific component protein-derived macrophage activating factor (GcMAF) has various functions including activation of M2-type macrophages and the improvement of motor disability. We tested whether activation of M2-type macrophage by GcMAF after brain ischemia induces beneficial effects. In the early phase of post-ischemia, GcMAF had no beneficial effects. In the late phase, it promoted the clearance of the infarct area; elevated the mRNA level of arginase-1 and increased CD163+ M2-like macrophages in the peri-infarct region. They co-localized with CD36+- and CD68+- but not Iba-1+ cells.. Treatment with GcMAF increased in the incorporation of BrdU and the appearance of NeuN+ and MAP2+ cells in the peri-infarct region mildly improved the neurological deficit. The activation of M2-like macrophages by GcMAF in the late phase may play a therapeutic role.

Research Products

• [Journal Article] Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study (2018)
  • Author(s): 1.Nagahiro S, Tada Y, Satomi J, Kinouchi T, Kuwayama K, Yagi K, Nakajima K, Matsushita N, Miyamoto T, Yamaguchi T, Shimada K, Korai M, Mure H, Okayama Y, Abe T, Harada M, Kitazato KT, Kanematsu Y
  • Journal Title: Stroke Cerebrovasc Dis Volume: - Issue: 8 Pages: 2134-2140
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.008
  • NAID: 120006961144
  • Peer Reviewed / Open Access
• [Journal Article] Biofeedback effect of hybrid assistive limb in stroke rehabilitation: A proof of concept study using functional near infrared spectroscopy (2018)
  • Author(s): Saita Kazuya、Morishita Takashi、Arima Hisatomi、Hyakutake Koichi、Ogata Toshiyasu、Yagi Kenji、Shiota Etsuji、Inoue Tooru
  • Journal Title: PLOS ONE Volume: 13 Issue: 1 Pages: e0191361-e0191361
  • DOI: 10.1371/journal.pone.0191361
  • Peer Reviewed / Open Access
• [Journal Article] Spot sign predicts rebleeding after endoscopic surgery for intracerebral hemorrhage (2018)
  • Author(s): Miki K, Yagi K, Nonaka M,Iwaasa M, Abe H,Morishita T,Arima H,Inoue T
  • Journal Title: J Neurosurge Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic Surgery via a Combined Frontal and Suboccipital Approach for Cerebellar Hemorrhage (2018)
  • Author(s): Nonaka M, Yagi1 K, Abe H, Miki K, Morishita T, Iwaasa M,Inoue T
  • Journal Title: Surg Neuro Int Volume: - Issue: 1 Pages: 68-68
  • DOI: 10.4103/sni.sni_346_17
  • Peer Reviewed / Open Access
• [Journal Article] Cerebral and spinal cavernomas associated with Klippel-Trenaunay syndrome: case report and literature review (2017)
  • Author(s): Yoshinaga Takaya、Yagi Kenji、Morishita Takashi、Abe Hiroshi、Nonaka Masani、Inoue Tooru
  • Journal Title: Acta Neurochirurgica Volume: 160 Issue: 2 Pages: 287-290
  • DOI: 10.1007/s00701-017-3408-5
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats (2017)
  • Author(s): Kinouchi Tomoya、Kitazato Keiko T.、Shimada Kenji、Yagi Kenji、Tada Yoshiteru、Matsushita Nobuhisa、Kurashiki Yoshitaka、Satomi Junichiro、Sata Masataka、Nagahiro Shinji
  • Journal Title: Transl Stroke Res Volume: - Issue: 3 Pages: 306-316
  • DOI: 10.1007/s12975-017-0577-8
  • NAID: 120007042447
  • Peer Reviewed / Open Access
• [Journal Article] Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats (2017)
  • Author(s): Maekawa Hidetsugu、Tada Yoshiteru、Yagi Kenji、Miyamoto Takeshi、Kitazato Keiko T.、Korai Masaaki、Satomi Junichiro、Hashimoto Tomoki、Nagahiro Shinji
  • Journal Title: Journal of Neuroinflammation Volume: 14 Issue: 1 Pages: 197-204
  • DOI: 10.1186/s12974-017-0966-7
  • Peer Reviewed / Open Access
• [Journal Article] Cryptic recanalization of chronic vertebral artery occlusion by head rotation (2017)
  • Author(s): Yagi K, Nakagawa H, Mure H, Okita S, Nagahiro S
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 26 Issue: 4 Pages: 60-61
  • DOI: 10.1016/j.jstrokecerebrovasdis.2016.12.034
  • Peer Reviewed
• [Journal Article] Coexistence of Quasi-moyamoya Disease and POEMS Syndrome in a Patient with Intracranial Hemorrhage: A Case Report and Literature Review (2017)
  • Author(s): Yamaguchi I, Satomi J, Yamamoto N, Yoshioka S, Tada Y, Yagi K, Kanematsu Y, Nagahiro S
  • Journal Title: NMC Case Report Journal Volume: 4 Issue: 1 Pages: 5-9
  • DOI: 10.2176/nmccrj.cr.2016-0106
  • NAID: 130005239937
  • ISSN: 2188-4226
  • Peer Reviewed
• [Journal Article] Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment (2017)
  • Author(s): Sogabe S, Satomi J, Tada Y, Kanematsu Y, Kuwayama K, Yagi K, Yoshioka S, Mizobuchi Y, Mure H, Yamaguchi I, Abe T, Yamamoto N, Kitazato KT, Kaji R, Harada M, Nagahiro S
  • Journal Title: Neuroradiology. Volume: － Issue: 6 Pages: 587-595
  • DOI: 10.1007/s00234-017-1828-9
  • Peer Reviewed / Open Access
• [Journal Article] DIAS-J Investigators Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke (2015)
  • Author(s): Mori E, Minematsu K, Nakagawara J, Hasegawa Y, Nagahiro S, Okada Y, Truelsen T, Lindsten A, Ogawa A, Yamaguchi T
  • Journal Title: Stroke Volume: 46 Issue: 9 Pages: 2549-2554
  • DOI: 10.1161/strokeaha.115.009917
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage (2015)
  • Author(s): Yagi K, Lidington D, Wan H, Fares JC, Meissner A, Sumiyoshi M, Ai J1, Foltz WD, Nedospasov SA, Offermanns S, Nagahiro S, Macdonald RL, Bolz SS
  • Journal Title: Stroke Volume: 46 Issue: 8 Pages: 2260-2270
  • DOI: 10.1161/strokeaha.114.006365
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intraoperative Arachnoid Plasty Has Possibility to Prevent Chronic Subdural Hematoma after Surgery for Unruptured Cerebral Aneurysms (2015)
  • Author(s): Yagi K, Irie S, Inagaki T, Ishii Y, Saito O, Lee T, Nakagawa H, Saito K, Nagahiro S
  • Journal Title: Neurologia medico-chirurgica Volume: 55 Issue: 6 Pages: 493-497
  • DOI: 10.2176/nmc.oa.2014-0455
  • NAID: 130005076045
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The accumulation of brain water-free sodium is associated with ischemic damage independent of the blood pressure in female rats (2015)
  • Author(s): Sumiyoshi M, Kitazato KT, Yagi K, Miyamoto T, Kurashiki Y, Matsushita N, Kinouchi T, Kuwayama K, Satomi J, Nagahiro S
  • Journal Title: Brain Res Volume: 1616 Pages: 37-44
  • DOI: 10.1016/j.brainres.2015.04.051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture (2015)
  • Author(s): Shimada K, Furukawa H, Wada K, Korai M, Wei Y, Tada Y, Kuwabara A, Shikata F, Kitazato KT, Nagahiro S, Lawton MT, Hashimoto T
  • Journal Title: Stroke Volume: 46 Issue: 6 Pages: 1664-1672
  • DOI: 10.1161/strokeaha.114.007722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PPARγ-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates Ischemic Brain Damage in Ovariectomized Rats (2015)
  • Author(s): Sumiyoshi M, Satomi J, Kitazato KT, Yagi K, Shimada K, Kurashiki Y, Korai M, Miyamoto T, Suzue R, Kuwayama K, Nagahiro S
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Issue: 6 Pages: 1187-1195
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.01.009
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan (2015)
  • Author(s): Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi J, Kitazato KT, Kageji T, Matsuura E, Nagahiro S
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Issue: 7 Pages: 1487-1492
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.015
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice (2015)
  • Author(s): Shimada K, Furukawa H, Wada K, Wei Y, Tada Y, Kuwabara A, Shikata F, Kanematsu Y, Lawton M, Kitazato K, Nagahiro S, Hashimoto T
  • Journal Title: J Cereb Blood Flow Metab Volume: 35 Issue: 7 Pages: 1163-1168
  • DOI: 10.1038/jcbfm.2015.30
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脳卒中に対す内視鏡下血腫除去術後の再出血リスクファクターの検討 (2018)
  • Author(s): 三木浩一、八木謙次、野中将、岩朝光利、安部洋、森下登史、有馬久富、井上亨
  • Organizer: 第43回日本脳卒中学会学術集会
• [Presentation] CEA後のkinking stenosisを危惧し、内径動脈のshortening procedure を施行した1例 (2018)
  • Author(s): 小林広昌、湧田尚樹、森下登史、八木謙次、安部洋、野中将、東登志夫、井上亨
  • Organizer: 第47回日本脳卒の外科学会学術集会
• [Presentation] 脳卒中慢性期運動麻痺に対する系図外直流電気刺激療法を利用したリハビリテーション (2018)
  • Author(s): 森下登史、百武光一、斉田和哉、八木謙次、安部洋、井上亨
  • Organizer: 第47回日本脳卒の外科学会学術集会
• [Presentation] 小脳出血に対する神経内視鏡手術の複合戦略 (2018)
  • Author(s): 野中将、天本宇昭、三木浩一、小林広昌、湧田尚樹、八木謙次、安部洋、岩朝光利、井上亨
  • Organizer: 第47回日本脳卒の外科学会学術集会
• [Presentation] 脳・脊髄に多発する症候性血管腫を呈したKlippel-Trenaunay syndromeの1例 (2017)
  • Author(s): 八木謙次、吉永貴也、森下登史、安部洋、野中将、東登志夫、井上亨
  • Organizer: 日本脳神経外科学会総会 第76回学術総会
• [Presentation] 後大脳動脈瘤・上小脳動脈瘤に対する複合的治療の問題点 (2017)
  • Author(s): 安部洋、松本徳彦、三木浩一、小林広昌、湧田尚樹、森下登史、八木謙次、野中将、岩朝光利、東登志夫、井上亨
  • Organizer: 日本脳神経外科学会総会 第76回学術総会
• [Presentation] Activation of M2 macrophages in the late phase of cerebral ischema may contribute to phagocytosis of infract area and neurogenesis (2016)
  • Author(s): Y. Kurashiki, K.T. Kitazato, K. Shimada, K. Yagi, Y. Tada, T. Kinouchi, M. Sumiyoshi, T. Miyamoto, T. Yamaguchi, J. Satomi, Y. Uto, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Italy(Venice)
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Porphyromonas gingivalis lipopolysaccharide enhances the rupture of intracranial aneurysms in rats (2016)
  • Author(s): T. Miyamoto, K.T. Kitazato, H. Maekawa, T. Yamaguchi, K. Shimada, K. Yagi, Y. Tada, Y. Kurashiki, S. Yoshioka, Y. Kanematsu, J. Satomi, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Italy(Venice)
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Activation of M2 macrophages in the late phase of cerebral ischema may contribute to phagocytosis of infract area and neurogenesis (2016)
  • Author(s): Y. Kurashiki, K.T. Kitazato, K. Shimada, K. Yagi, Y. Tada, T. Kinouchi, M. Sumiyoshi, T. Miyamoto, T. Yamaguchi, J. Satomi, Y. Uto, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Venice, Italy
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Porphyromonas gingivalis lipopolysaccharide enhances the rupture of intracranial aneurysms in rats (2016)
  • Author(s): T. Miyamoto, K.T. Kitazato, H. Maekawa, T. Yamaguchi, K. Shimada, K. Yagi, Y. Tada, Y. Kurashiki, S. Yoshioka, Y. Kanematsu, J. Satomi, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Venice, Italy
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Early Morphological Changes in Cerebral Arteries of Cerebral Aneurysm Rupture Model Rats (2016)
  • Author(s): H. Maekawa, T. Miyamoto, K.T. Kitazato, K. Yagi, Y. Tada, K. Shimada, J. Satomi, S. Nagahiro
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Impact of Periodontal Disease and －Bacteria on Intracranial Aneurysms (2016)
  • Author(s): S. Yoshioka, Y. Tada, J. Satomi, K. Yagi, K. Naruishi, K. Kuwayama, K. T. Kitazato, T. Miyamoto, Y. Kanematsu, M. Harada, T. Nagata, S. Nagahiro
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] A Pilot Study of the Mineralocorticoid Receptor Blocker Eplerenone in Hypertensive Patients with Unruptured Cerebral Aneurysms (2016)
  • Author(s): J. Satomi, Y. Tada, Y. Kanematsu, K. Kuwayama, K. Yagi, T. Kinouchi, K. Nakajima, N. Matsushita, T. Miyamoto, T. Yamaguchi, M. Korai, H. Mure, K. T. Kitazato, S. Nagahiro
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] 3D structure of vasa vasorum in thrombosed rat cerebral aneurysms (2016)
  • Author(s): H. Maekawa, T. Miyamoto, K.T. Kitazato, S. Nagahiro
  • Organizer: ABC－WIN Seminar 2016
  • Place of Presentation: Paris, France
  • Year and Date: 2016-01-17
  • Int'l Joint Research