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

Yongsheng Zhu; Peng Yan; Rui Wang; Jianghua Lai; Hua Tang; Xu Xiao; Rongshan Yu; Xiaorui Bao; Feng Zhu; Kena Wang; Ye Lu; Jie Dang; Chao Zhu; Rui Zhang; Wei Dang; Bao Zhang; Quanze Fu; Qian Zhang; Chongao Kang; Yujie Chen; Xiaoyu Chen; Qing Liang; Kejia Wang

doi:10.1016/j.cell.2022.12.030

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. Epub 2023 Jan 19.

Authors

Yongsheng Zhu¹, Peng Yan¹, Rui Wang², Jianghua Lai¹, Hua Tang³, Xu Xiao⁴, Rongshan Yu⁴, Xiaorui Bao⁵, Feng Zhu⁶, Kena Wang¹, Ye Lu¹, Jie Dang⁷, Chao Zhu⁸, Rui Zhang⁹, Wei Dang¹⁰, Bao Zhang¹, Quanze Fu⁵, Qian Zhang⁵, Chongao Kang⁵, Yujie Chen⁵, Xiaoyu Chen⁵, Qing Liang¹¹, Kejia Wang¹²

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid / administration & dosage
Animals
Interferon-gamma* / metabolism
Mice
Opioid-Related Disorders* / metabolism
Opioid-Related Disorders* / pathology
Substance Withdrawal Syndrome*
T-Lymphocytes, Regulatory*

Substances

Analgesics, Opioid
Interferon-gamma