Unmet Needs in the Beyond VEGF Era: Macrophage Educational Therapy for Retinal Fibrosis and Ischemia

• Project/Area Number: 17K11456
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyushu University
• Principal Investigator: Nakao Shintaro 九州大学, 医学研究院, 講師 (50583027)
• Co-Investigator(Kenkyū-buntansha): 園田 康平 九州大学, 医学研究院, 教授 (10294943) ; 吉田 茂生 久留米大学, 医学部, 教授 (50363370)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 糖尿病網膜症 / 加齢黄斑変性 / マクロファージ / 抗VEGF療法 / 炎症 / 網膜虚血 / 網膜下線維化 / シングルセル / 上皮間葉移行 / 細胞・組織 / 糖尿病 / トランスレーショナルリサーチ

Outline of Final Research Achievements

In a retinal ischemia mouse model, we observed infiltration of M1and M2 macrophages and increased expression of M1and M2 marker at mRNA level. We also observed that M1 macrophages were significantly present in the ischemic area. Gadolinium chloride, which mainly deletes M1 macrophages, was found to improve ischemia, suggesting that M1 macrophages could be a therapeutic target for retinal ischemia.
Fate mapping analysis in a subretinal fibrosis mouse model revealed that myofibroblast, which is a major component of fibrosis, is derived from RPE. The process involves epithelial-mesenchymal transition via ROCK suggesting that ROCK is a candidate drug for molecular target of subretinal fibrosis.

Academic Significance and Societal Importance of the Research Achievements

糖尿病網膜症や加齢黄斑変性などの網膜疾患は近年抗VEGF療法の汎用により失明を免れる症例も増えてきた。しかし、抗VEGF療法においても治癒しない網膜虚血、網膜下線維化は現在のUnmet needsと言える。本研究はこれらの細胞レベルでのメカニズムを一部明らかにした。また今後の治療開発への一助となると考える。

Research Products

• [Journal Article] Claudin-5 Redistribution Induced by Inflammation Leads to Anti-VEGF-Resistant Diabetic Macular Edema. (2020)
  • Author(s): Arima M, Nakao S, Yamaguchi M, Feng H, Fujii Y, Shibata K, Wada I, Kaizu Y, Ahmadieh H, Ishibashi T, Stitt AW, Sonoda KH.
  • Journal Title: Diabetes Volume: 69 Issue: 5 Pages: 981-999
  • DOI: 10.2337/db19-1121
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Branch retinal artery occlusion in the untreated contralateral eye following aflibercept injections during heparin treatment: Possible contribution of a heparin-induced thrombocytopenia-like condition. (2020)
  • Author(s): Nakao S, Yoshimitsu M, Kaizu Y, Wada I, Yamaguchi M, Sonoda KH.
  • Journal Title: Am J Ophthalmol Case Rep. Volume: 16 Pages: 100549-100549
  • DOI: 10.1016/j.ajoc.2019.100549
  • Peer Reviewed / Open Access
• [Journal Article] Innate immune response in retinal homeostasis and inflammatory disorders. (2020)
  • Author(s): Murakami Y, Ishikawa K, Nakao S, Sonoda KH.
  • Journal Title: Prog Retin Eye Res. Volume: 74 Pages: 100778-100778
• [Journal Article] Microaneurysm Imaging using Multiple En Face Optical Coherence Tomography Angiography Image Averaging: Morphology and Visualization (2019)
  • Author(s): Kaizu Y, Nakao S, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Kishimoto J, Hisatomi T, Sonoda KH
  • Journal Title: Ophthalmology Retina Volume: 4 Issue: 2 Pages: 175-186
  • DOI: 10.1016/j.oret.2019.09.010
  • Peer Reviewed
• [Journal Article] Flow Density in Optical Coherence Tomography Angiography is Useful for Retinopathy Diagnosis in Diabetic Patients. (2019)
  • Author(s): Kaizu Y, Nakao S, Arima M, Hayami T, Wada I, Yamaguchi M, Sekiryu H, Ishikawa K, Ikeda Y, Sonoda KH.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 8668-8668
  • DOI: 10.1038/s41598-019-45194-z
  • Peer Reviewed / Open Access
• [Journal Article] apillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography (2018)
  • Author(s): Kaizu Y, Nakao S*, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH.
  • Journal Title: Acta Ophthalmol. Volume: 印刷中 Issue: 5
  • DOI: 10.1111/aos.14041
  • Peer Reviewed
• [Journal Article] Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy. (2018)
  • Author(s): Kaizu Y, Nakao S*,, Sekiryu H, Wada I, Yamaguchi M, Hisatomi T, Ikeda Y, Kishimoto J, Sonoda KH.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 256 Issue: 12 Pages: 2275-2282
  • DOI: 10.1007/s00417-018-4122-6
  • Peer Reviewed
• [Journal Article] Microaneurysm Detection in Diabetic Retinopathy using OCT Angiography May Depend on Intra-microaneurysm Turbulence. (2018)
  • Author(s): Nakao S*, Yoshida S, Kaizu Y, Yamaguchi M, Wada I, Ishibashi T, Sonoda KH.
  • Journal Title: Ophthalmology Retina Volume: 2 Pages: 1171-1173
• [Journal Article] Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels (2018)
  • Author(s): Nakao Shintaro、Zandi Souska、Sun Dawei、Hafezi-Moghadam Ali
  • Journal Title: The FASEB Journal Volume: 32 Issue: 1 Pages: 143-154
  • DOI: 10.1096/fj.201601229r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Imaging of Retinal Vascular Layers: Adaptive Optics Scanning Laser Ophthalmoscopy Versus Optical Coherence Tomography Angiography (2017)
  • Author(s): Kaizu Yoshihiro、Nakao Shintaro、Wada Iori、Yamaguchi Muneo、Fujiwara Kohta、Yoshida Shigeo、Hisatomi Toshio、Ikeda Yasuhiro、Hayami Takehito、Ishibashi Tatsuro、Sonoda Koh-hei
  • Journal Title: Translational Vision Science & Technology Volume: 6 Issue: 5 Pages: 2-2
  • DOI: 10.1167/tvst.6.5.2
  • Peer Reviewed / Open Access
• [Journal Article] Optical Coherence Tomography Angiography Reveals Spatial Bias of Macular Capillary Dropout in Diabetic Retinopathy (2017)
  • Author(s): Kaizu Yoshihiro、Nakao Shintaro、Yoshida Shigeo、Hayami Takehito、Arima Mitsuru、Yamaguchi Muneo、Wada Iori、Hisatomi Toshio、Ikeda Yasuhiro、Ishibashi Tatsuro、Sonoda Koh-Hei
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 58 Issue: 11 Pages: 4889-4889
  • DOI: 10.1167/iovs.17-22306
  • Peer Reviewed / Open Access
• [Journal Article] Rho-Kinase/ROCK as a Potential Drug Target for Vitreoretinal Diseases (2017)
  • Author(s): Yamaguchi Muneo、Nakao Shintaro、Arima Mitsuru、Wada Iori、Kaizu Yoshihiro、Hao Feng、Yoshida Shigeo、Sonoda Koh-hei
  • Journal Title: Journal of Ophthalmology Volume: 2017 Pages: 1-8
  • DOI: 10.1155/2017/8543592
  • Peer Reviewed / Open Access
• [Presentation] Local Proliferation of CD206+ CX3CR1+ Macrophages at the Vitreoretinal Interface in Diabetic Retinopathy (2019)
  • Author(s): Nakao S, Yamaguchi M, Wada I, Kaizu Y, Arima M, Ishikawa K, Nakama T, Shiraishi W, Yamasaki R, Kira J, Ishibashi T, Sonoda KH
  • Organizer: ARVO
  • Int'l Joint Research
• [Presentation] Local Proliferation of Macrophages at the Vitreal Interface in Diabetic Retinopathy (2019)
  • Author(s): Nakao S
  • Organizer: Aegean Retina XVI
  • Int'l Joint Research / Invited
• [Presentation] Hyperreflective membrane at Vitreoretinal Interface Contributes to Retinal Thickness in DME but not Response to IVR Therapy : A Ultra High-Resolution Optical Coherence Tomography Study (2019)
  • Author(s): Nakao S
  • Organizer: The 12th Joint Meeting of Chinese-Japanese-Korean Ophthalmologists
  • Int'l Joint Research
• [Presentation] Microaneurysm Imaging using Multiple En Face OCTA Image Averaging: Morphology and Visualization (2019)
  • Author(s): Nakao S, Kaizu Y, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Sonoda KH
  • Organizer: 52th Retina Society Meeting
  • Int'l Joint Research
• [Presentation] 糖尿病網膜症におけるCD206+CX3CR1+ 硝子体界面マクロファージ局所増殖 (2019)
  • Author(s): 山口宗男, 中尾新太郎, 和田伊織, 海津嘉弘, 有馬充, 石川桂二郎, 中間崇仁, 白石渉, 山崎亮, 吉良潤一, 石橋達朗, 園田康平
  • Organizer: 日本眼科学会総会
• [Presentation] Microaneurysm Detection in Diabetic Retinopathy using OCT Angiography May Depend on Intra-microaneurysm Turbulence (2018)
  • Author(s): Nakao S, Yoshida S, Kaizu Y, Yamaguchi M, Wada I, Ishibashi T, Sonoda KH
  • Organizer: Retina Society
  • Int'l Joint Research
• [Presentation] OCT angiography detects re-dilation of choroidal neovasculatures before exudative recurrence in multifocal choroiditis with panuveitis: a case report (2018)
  • Author(s): Nakamura S, Nakao S, Shiose S, Kohno RI, Hasegawa E, Kano K, Kaizu Y, Seki E, Sonoda KH
  • Organizer: The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
  • Int'l Joint Research
• [Presentation] Microaneurysms Imaging in Diabetic Retinopathy using Multiple en face Optical Coherence Tomography Angiography Image Averaging (2018)
  • Author(s): Kaizu Y, Nakao S, Arima M, Wada I, Yoshitomi K, Sugino M, Hashiguchi N, Hirashima Kota, Sonoda KH
  • Organizer: The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
  • Int'l Joint Research
• [Presentation] The evaluation of disease activity in exudative age-related macular degeneration using en face hyperreflective foci (2018)
  • Author(s): Wada I, Nakao S, Shiose S, Kaizu Y, Yamaguchi M, Arima M, Ishikawa K, Kano K, Oshima Yuji, Ishibashi T, Sonoda KH
  • Organizer: The 11th Joint Meeting of Japan-China-Korea Ophthalmologists
  • Int'l Joint Research