Jie Y, Lai ZW, Zhou W, Li YC, Zhong BL, Zeng XX, Jiang Q. Neuroimmune synapse and modulation by anesthetics: Inflammatory mechanisms and therapeutic perspectives for postoperative neurocognitive disorders. World J Psychiatry 2026; 16(4): 115567 [DOI: 10.5498/wjp.v16.i4.115567]
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Apr 19, 2026 (publication date) through Mar 30, 2026
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World Journal of Psychiatry
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2220-3206
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Jie Y, Lai ZW, Zhou W, Li YC, Zhong BL, Zeng XX, Jiang Q. Neuroimmune synapse and modulation by anesthetics: Inflammatory mechanisms and therapeutic perspectives for postoperative neurocognitive disorders. World J Psychiatry 2026; 16(4): 115567 [DOI: 10.5498/wjp.v16.i4.115567]
Yao Jie, Wen Zhou, You-Chun Li, Bao-Lin Zhong, Qiong Jiang, Department of Anesthesiology, Ganzhou People’s Hospital, Ganzhou 341000, Jiangxi Province, China
Zhi-Wei Lai, Department of Orthopedics, Ganzhou Hospital of Traditional Chinese Medicine, Ganzhou 341000, Jiangxi Province, China
Xin-Xing Zeng, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Jie Y, Lai ZW, Zhou W, Li YC, and Zhong BL drafted the manuscript and performed the major revisions; Lai ZW and Zhou W prepared and revised the figures; Jie Y, Li YC, Zhong BL, and Zeng XX conducted the literature search and data curation; Jiang Q and Jie Y conceived the study, supervised the project, and critically reviewed and edited the manuscript. All authors discussed the proposed scope and content of the article before drafting, and have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Received: October 20, 2025 Revised: November 13, 2025 Accepted: December 25, 2025 Published online: April 19, 2026 Processing time: 161 Days and 10.9 Hours
Abstract
Postoperative delirium and postoperative cognitive dysfunction are common complications after anesthesia and surgery, particularly in older adults, and they substantially impair recovery quality and long-term outcomes. Neuroinflammation is widely recognized as a central mechanism, yet its origins and regulatory hubs remain incompletely defined. This review introduces the emerging concept of the “neuroimmune synapse (NIS)” as a critical interface that links immune regulation within the central nervous system to neuronal function, and it advances a new perspective on its role in anesthesia and surgery related neuroinflammation and cognitive impairment. We delineate the structural basis of the NIS, which is primarily constituted by microglia, astrocytes, and neurons. We summarize key signaling pathways, including the CX3C chemokine ligand 1/CX3CR1 and CD200/CD200R axes, the complement cascade, and the triggering receptor expressed on myeloid cells 2/DNAX activation protein of 12 kDa complex, and we outline their core physiological roles in maintaining synaptic homeostasis and immune surveillance. We then focus on the potential direct and indirect effects of different classes of anesthetics, including inhalational agents, propofol, benzodiazepines, ketamine, dexmedetomidine, and opioids, on the structure and function of the NIS, and analyze how these agents may disrupt neuroimmune dialogue. We propose that anesthesia and surgery act as combined stressors that perturb NIS function, for example by inducing aberrant microglial activation, promoting excessive release of proinflammatory mediators, and driving over-pruning of synapses. These processes can initiate and sustain neuroinflammatory cascades in the brain, leading to synaptic dysfunction and loss in key regions such as the hippocampus and prefrontal cortex, which represents a core pathological link to postoperative delirium and cognitive impairment. A NIS centered framework provides a new explanation for the vulnerability of high-risk populations, particularly older adults, and highlights potential avenues for intervention through optimized anesthetic strategies, such as agent selection and multimodal analgesia, or through targeting pivotal synaptic immune mediators, including CX3CR1, triggering receptor expressed on myeloid cells 2, and complement components. This review aims to catalyze research across disciplines and to establish a conceptual basis for innovative approaches to prevent and treat postoperative neurocognitive complications.
Core Tip: This review reinterprets postoperative neurocognitive disorders through the concept of the neuroimmune synapse (NIS), the microglia, astrocyte, and neuron interface coordinating immune and neuronal signaling. We synthesize evidence on NIS pathways (CX3C chemokine ligand 1/CX3CR1, CD200/CD200R, complement, triggering receptor expressed on myeloid cells 2/DNAX activation protein of 12 kDa), show how anesthesia combined with surgical stress perturbs NIS function, and link aberrant microglial activation, excessive synaptic pruning, and hippocampal and prefrontal dysfunction to postoperative neurocognitive disorders. We further outline how distinct anesthetic classes modulate NIS structure and signaling, and propose testable interventions: Agent selection, multimodal analgesia, and targeting CX3CR1, triggering receptor expressed on myeloid cells 2, and complement to restore synaptic homeostasis.
