Searching and understanding of physiological function of secreted molecule(s) from CX3CR1+ phagocyte

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16276
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: The University of Tokyo
• Principal Investigator: MORITA Naoki 東京大学, 定量生命科学研究所, 助教 (80845107)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 粘膜免疫 / 腸内細菌 / 自然免疫

Outline of Final Research Achievements

Intestinal microbiota plays a vital role in maintaining the physiological homeostasis of our body. The maintenance of a homeostatic environment in the intestinal lumen which harbors pathogenic and non-pathogenic microbiota, is regulated by host cell-derived secretory molecules
I found that intestinal CX3CR1+ phagocyte which take up luminal antigens by protruding their dendrites into the lumen, highly expressed Group IID secreted PLA2 (PLA2G2D). PLA2G2D work as not only enzyme of lipase but also antimicrobial molecule to gram-positive bacteria. Based on the function of CX3CR1+ phagocyte and expression of PLA2G2D in CX3CR1+ phagocyte. I observed that Pla2g2d -/- mice show dysbiosis in small intestinal microbiota associated with increasing of gram-positive microbiota at ageing. Pla2g2d -/- mice onset nonalcoholic fatty liver disease (NAFLD) and progression of hepatocarcinoma with increasing of senescent cells in a gram-positive microbiota dependent manner.

Free Research Field

粘膜免疫

Academic Significance and Societal Importance of the Research Achievements

申請者は小腸腸管に存在する貪食細胞の一種であるCX3CR1+細胞が分泌型PLA2G2D分子を高発現していることを明らかにした。分泌型PLA2G2D分子はグラム陽性菌に対して抗菌活性を持つことから、リステリア菌に対する感染実験を行なったところ、野生型マウスに比較性して分泌型PLA2G2D分子欠損マウスは高い感受性を示すことが明らかになった。また分泌型PLA2G2D分子欠損マウスは加齢に伴うグラム陽性腸内菌の増加やそれに伴う肝臓疾患の発症・増悪することを明らかにした。これらの結果から、正常な腸内細菌叢の維持にCX3CR1+細胞由来の分泌型PLA2G2D分子が重要であることが示唆された。