Mechanism of dying cell removal by inflammatory microglia
Project/Area Number |
18K06891
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 48030:Pharmacology-related
|
Research Institution | Hiroshima University |
Principal Investigator |
Hide Izumi 広島大学, 医系科学研究科(医), 講師 (20253073)
|
Co-Investigator(Kenkyū-buntansha) |
酒井 規雄 広島大学, 医系科学研究科(医), 教授 (70263407)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
|
Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
Keywords | ミクログリア / 炎症 / 貪食 / P2Y2受容体 / AXL受容体 / ATP / スラミン / ニューロン |
Outline of Final Research Achievements |
In most brain diseases, microglia become inflammatory and their excessive phagocytosis could induce unnecessary death of viable neurons. Live imaging demonstrated that LPS-stimulated microglia actively removed dying cells and neurons. A non-selective P2 receptor antagonist, suramin, and a selective P2Y2 receptor antagonist, AR-C118925, suppressed dying cell removal by LPS-stimulated microglia more potently than that by unstimulated microglia. LPS stimulation induced trafficking of P2Y2 receptor to the plasma membrane and upregulation of P2Y2 receptor mRNA expression in microglia. LPS stimulation decreased MER and increased AXL expressions, indicating that microglia preferentially utilize AXL under inflammatory condition. AR-C118925 suppressed LPS-stimulated Axl upregulation possibly via inhibiting PYK2. Together, P2Y2 receptor may play an important role in dying cell removal at least through mediating upregulation of AXL phagocytic receptor via PYK2 in inflammatory microglia.
|
Academic Significance and Societal Importance of the Research Achievements |
超高齢化に伴い急増が懸念されるアルツハイマー病やパーキンソン病などの神経変性疾患、脳梗塞、自閉症や統合失調症に至るほとんどすべての精神神経疾患においてミクログリアの関与が示唆されている。炎症により過剰に活性化されたミクログリアは生理的な貪食とは異なる貪食能を獲得し、病態形成に関与すると考えられる。本研究成果は、これまで不明であった炎症性貪食能獲得のメカニズムを明らかにするものであり、炎症制御機構の理解において大きな学術的意義を持つ。また、今回明らかにしたP2Y2受容体はアルツハイマー病や自閉症など炎症や貪食が関わる神経疾患の新たな治療標的となる可能性があり今後の展開が期待される。
|
Report
(4 results)
Research Products
(53 results)
-
-
-
[Journal Article] Syntaxin 3 interacts with serotonin transporter and regulates its function.2021
Author(s)
Motoike, S., Taguchi, K., Harada, K., Asano, M., Hide, I. Tanaka, S. Irifune, M. and Sakai,
-
Journal Title
J. Pharmacol. Sci.
Volume: 145
Issue: 4
Pages: 297-307
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
[Journal Article] Component of nicotine-induced intracellular calcium elevation mediated throughα3- andα5-containing nicotinic acetylcholine receptors are regulated by cyclic AMP in SH-SY 5Y cells2020
Author(s)
Takahashi, T., Yoshida, T., Harada, K., Miyagi, T., Hashimoto, K., Hide, I., Tanaka, S., Irifune, M. and Sakai, N.
-
Journal Title
PLos One
Volume: 15
Issue: 11
Pages: e0242349-e0242349
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
-
[Journal Article] The Role of Cysteine String Protein Alpha (CSPα) Phosphorylation at Serine 10, and 34, by Protein Kinase Cγ for Presynaptic Maintenance.2018
Author(s)
Shirafuji T, Ueyama T, Adachi N, Yoshino KI, Sotomaru Y, Uwada J, Kaneoka A, Ueda T, Tanaka S, Hide I, Saito N, Sakai N
-
Journal Title
J. Neurosci.
Volume: 38
Issue: 2
Pages: 278-290
DOI
Related Report
Peer Reviewed
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[Presentation] Neuroscience 20182018
Author(s)
Shigeru Tanaka, Naoto Shimada, Masahiro Yamamoto, Tatsuhiro Miyagi, Hiroko, Shiraki, Izumi Hide, Norio Sakai
Organizer
Neuroscience 2018
Related Report
Int'l Joint Research
-
-
-
-