Bone marrow-derived myeloid cells entering the brain via the choroid plexus are involved in neuroinflammatory and neurodegenerative conditions

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kyorin University
• Principal Investigator: Shimada Atsuyoshi 杏林大学, 保健学部, 教授 (50311444)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脈絡叢 / 神経炎症 / 敗血症関連脳症

Outline of Final Research Achievements

Systemic inflammation such as sepsis is a risk factor for encephalopathy. However, it remains to be revealed how systemic inflammation induces changes in brain microenvironment. In the present study, we aimed to investigate the mechanism underlying systemic inflammation-induced pro-inflammatory changes in the brain microenvironment and to compare the mechanisms between adult and immature brains. Our experimental studies using adult mice indicated that the choroid plexus, a organ to produce cerebrospinal fluid play a key role to transmit systemic inflammation to brain parenchyma by cytokine-mediated intercellular stimulation between stromal and epithelial cells. On the other hand, elevation in the brain tissue cytokine concentration lasted longer in the immature brains when newborn mice were challenged with systemic inflammation. It should be noted that the main cell population involved in the cytokine production were vascular endothelial cells in immature brains.

Free Research Field

実験病理学、病態神経科学

Academic Significance and Societal Importance of the Research Achievements

敗血症は全世界で年間5000万人もの人々が罹患し、1000万人が死亡する重大な疾患である。ICUで治療を受ける敗血症患者の約50%で脳症状が発生し、重症化の初期徴候であるが、画像上で脳に病変が確認できるのは約50%と謎の多い病態である。とりわけ早産児は免疫力がまだ弱く、敗血症をはじめとする全身性炎症を発症すると、発達途上の脳に何らかの病変が誘発され、脳性麻痺や神経発達症などの後遺障害をのこす。この際に全身性炎症の影響を脳に伝達する機序は不明である。我々は、ヒトでは早産児に相当する新生仔マウスを用いて新生児敗血症モデルを作製し、全身性炎症を脳に伝達する未熟脳に特有な機序の一端を明らかにした。