摘要
Excitatory amino acid transporters(EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues.However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study,we demonstrated that LPS stimulation increases expression of EAAT2(coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation. Mechanistically, lysosomal EAAT2 mediates lysosomal glutamate and aspartate efflux to maintain V-ATPase activation, which sustains macropinocytosis and mTORC1. We also found that mice with myeloid depletion of Slc1a2 show alleviated inflammatory responses in LPS-induced systemic inflammation and high-fat diet induced obesity. Notably, patients with type Ⅱ diabetes(T2D) have a higher level of expression of lysosomal EAAT2 and activation of mTORC1 in blood macrophages. Taken together, our study links the subcellular location of amino acid transporters with the fate decision of immune cells,which provides potential therapeutic targets for the treatment of inflammatory diseases.
基金
supported by the National Natural Science Foundation of China (32225047 and U22A20510)
Laboratory of Lingnan Modern Agriculture Project (NT2021005)
National Center of Technology Innovation for Pigs (NCTIP-XD/B13)
double first-class discipline promotion project (2023B10564001)。
作者简介
Corresponding author:Wenkai Ren received his Ph.D.from Institute of Subtropical Agriculture,Chinese Academy of Sciences.He is currently a professor at South China Agricultural University and his work focuses on immuno-metabolism.E-mail address:renwenkai19@scau.edu.cn;Zhending Gan is a Ph.D.candidate at College of Animal Science,South China Agricultural University.His research interest focuses on immuno-metabolism.contributed equally to this work;Yan Guo is a Ph.D.candidate at College of Animal Science,South China Agricultural University.Her research interest focuses on immuno-metabolism.contributed equally to this work.
