Opioid-induced fragile-like regulatory T cells contribute to withdrawal

  • Cell. 2023 Feb 2;186(3):591-606.e23. doi: 10.1016/j.cell.2022.12.030.
Yongsheng Zhu  1 ,  Peng Yan  1 ,  Rui Wang  2 ,  Jianghua Lai  1 ,  Hua Tang  3 ,  Xu Xiao  4 ,  Rongshan Yu  4 ,  Xiaorui Bao  5 ,  Feng Zhu  6 ,  Kena Wang  1 ,  Ye Lu  1 ,  Jie Dang  7 ,  Chao Zhu  8 ,  Rui Zhang  9 ,  Wei Dang  10 ,  Bao Zhang  1 ,  Quanze Fu  5 ,  Qian Zhang  5 ,  Chongao Kang  5 ,  Yujie Chen  5 ,  Xiaoyu Chen  5 ,  Qing Liang  11 ,  Kejia Wang  12
Affiliations
  • 1. National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, Shaanxi 710115, China.
  • 2. Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Informatics, Xiamen University, Xiamen, Fujian 361005, China.
  • 3. Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710117, China.
  • 4. National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Informatics, Xiamen University, Xiamen, Fujian 361005, China.
  • 5. Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
  • 6. Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 7. School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
  • 8. Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • 9. Department of Emergency Medicine, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
  • 10. The Sixth Ward, Xi'an Mental Health Center, Xi'an, Shannxi 710100, China.
  • 11. Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
  • 12. Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
PMID: 36669483 DOI: 10.1016/j.cell.2022.12.030
Abstract

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.

Keywords
interferon-γ; opioid; regulatory T cell; synaptic plasticity; withdrawal symptom.
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