2. Academic Validation
  3. 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.
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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