Exosome mediated Innate/inflammatory cross talk between macrophages (Mps) and iPS-derived RPE cells: Proposal of new trait for the pathogenesis of age-related macular degeneration (AMD)

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11463
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: HAMURO JUNJI 京都府立医科大学, 医学(系)研究科(研究院), 客員教授 (80536095)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: マクロファージ / 網膜色素上皮細胞 / 加齢黄斑変性 / エキソゾーム / miRNA / 炎症性サイトカイン / 血管新生抑制因子

Outline of Final Research Achievements

The pathogenesis of AMD is aggravated by chronic inflammation. Intact RPE down-regulates TNF-a production by choroid-infiltrating Mps, whereas degenerated RPE is devoid of this regulatory function. CD63+ exosome in co-cultures were detected by western blot or FACS analysis, in accordance with the elevated production of nanoparticles detected by Nonosight. The production of MCP-1, IL-6, IL-8 and VEGF from RPE were elevated in the co-culture with Mps, while that of TNF-a and PEDF were reduced. The modulation of these cytokines was not visible in the double chambered system isolated with 0.03 mm membrane filters, while those of PEDF, IL-8 and TNF were significant even in the double chambered system. These results, together with the similar results in the co-cultures of Mps with ARPE19, indicate the presence of cross talk between Mps and RPE cells in human systems. RPE secreted exosome displays a critical role in the triggering of a vicious inflammatory cytokine induction cycle.

Free Research Field

免疫学、炎症学、再生医療

Academic Significance and Societal Importance of the Research Achievements

黄斑局所の恒常性維持に不可欠な網膜色素上皮細胞(RPE) とマクロフアージ（Mps）系とのネットワーク破綻の一部を、RPE./Mps共培養系を用い深化させ、AMD擬似病態のin vitroでの再構成に成功した。RPEによるMps炎症惹起能の抑制（免疫特権の成立）、補体活性化抑制因子産生増強vs補体活性化因子産生抑制作用、抗血管新生作用を有するPEDF 産生増強vs血管新生増強因子VEGF産生抑制という精妙な機能可塑性の破綻の分子機構の骨格を解明した。RPE/Mp間のパラクリンループ形成における細胞外小胞体粒子の寄与を明確にできたことは、加齢黄斑変性の先制医療に有益な独創的医療技術に繋がる。