2. Academic Validation
  3. Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation

Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation

  • Mol Cell. 2020 Apr 2;78(1):42-56.e6. doi: 10.1016/j.molcel.2020.01.022.
Yuqing Wu 1,  Yingchao Hu 1,  Bingwei Wang 2,  Sheng Li 1,  Chunmei Ma 1,  Xue Liu 1,  Paul N Moynagh 3,  Jiawei Zhou 4,  Shuo Yang 5
Affiliations

Affiliations

  • 1 Department of Immunology, Key Laboratory of Immunological Environment and Disease, State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China.
  • 2 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: bingweiwang@njucm.edu.cn.
  • 3 Kathleen Lonsdale Institute for Human Health Research, Department of Biology, National University of Ireland Maynooth, Maynooth, Ireland; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
  • 4 Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of Immunology, Key Laboratory of Immunological Environment and Disease, State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China. Electronic address: shuoyang@njmu.edu.cn.
PMID: 32035036 DOI: 10.1016/j.molcel.2020.01.022
Abstract

The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-κB activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-κB and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis.

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