1. Academic Validation
  2. Opioid-induced fragile-like regulatory T cells contribute to withdrawal

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

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: liangqing@xmu.edu.cn.
  • 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: wangkejia@xmu.edu.cn.
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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