Zhang AY, Xie CY, Song X, Guo ZH, Shi YR, Wang SY, Yang GH, Liu Y, Xu TC. Triggering receptor expressed on myeloid cells 2-driven pancreatic macrophage crosstalk: Key regulator of obesity pathophysiology and metabolic dysregulation. World J Biol Chem 2026; 17(2): 118705 [DOI: 10.4331/wjbc.v17.i2.118705]
Corresponding Author of This Article
Tian-Cheng Xu, MD, PhD, President, Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China. xtc@njucm.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
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review-article
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Zhang AY, Xie CY, Song X, Guo ZH, Shi YR, Wang SY, Yang GH, Liu Y, Xu TC. Triggering receptor expressed on myeloid cells 2-driven pancreatic macrophage crosstalk: Key regulator of obesity pathophysiology and metabolic dysregulation. World J Biol Chem 2026; 17(2): 118705 [DOI: 10.4331/wjbc.v17.i2.118705]
Ao-Yun Zhang, Cong-Yi Xie, Xiao Song, Zi-Han Guo, Yu-Rou Shi, Shuai-Yan Wang, Yun Liu, Tian-Cheng Xu, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Guan-Hu Yang, Department of Specialty Medicine, Ohio University, Athens, OH 45701, United States
Guan-Hu Yang, School of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau 999078, China
Co-first authors: Ao-Yun Zhang and Cong-Yi Xie.
Co-corresponding authors: Yun Liu and Tian-Cheng Xu.
Author contributions: Zhang AY and Xie CY contributed equally to this manuscript as co-first authors; Liu Y and Xu TC conceptualized and designed this review, and they contributed equally to this manuscript as co-corresponding authors; Zhang AY, Xie CY, Shi YR, Song X, and Guo ZH wrote the first draft of the manuscript. Zhang AY was responsible for the core conceptualization and overall framework, while Xie CY was responsible for the creation of figures in the initial draft. Both authors contributed significantly to the writing of the core content of the manuscript and coordinated the writing process, making essential and irreplaceable contributions to the completion of the project, and thus qualified as the co-first authors of the paper. Liu Y played key roles in quality control, academic depth enhancement, and final manuscript coordination, while Xu TC focused on the academic depth and content rigor of the review, assuming key responsibilities for academic oversight, coordinating feedback from all authors on revised versions, leading responses to reviewer comments during the submission process, and guiding further improvements to the manuscript, ensuring the academic quality and publication standards of the review. All authors have reviewed and approved the final version of the manuscript.
Supported by the National Natural Science Foundation, No. 82305376; the Youth Talent Support Project of the China Acupuncture and Moxibustion Association, No. 2024-2026ZGZJXH-QNRC005; the 2024 Jiangsu Province Youth Science and Technology Talent Support Project, No. JSTJ-2024-380; and Jiangsu Science and Technology Think Tank Program Project, No. 2025-20-35.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Tian-Cheng Xu, MD, PhD, President, Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China. xtc@njucm.edu.cn
Received: January 9, 2026 Revised: February 25, 2026 Accepted: May 12, 2026 Published online: June 5, 2026 Processing time: 146 Days and 19 Hours
Abstract
Obesity, a global epidemic, is closely linked to metabolic complications like insulin resistance and type 2 diabetes. Pancreatic dysfunction (impaired islet secretion and local inflammation) is central to this deterioration, yet the underlying mechanisms remain unclear. Pancreatic macrophages regulate tissue inflammation and metabolic homeostasis, but their context-specific polarization in obesity is undefined. This review discusses the role of triggering receptor expressed on myeloid cells 2 (TREM2) in modulating pancreatic macrophage behavior in the context of obesity, based on findings from diet-induced obese mouse models and ex vivo pancreatic analyses. Emerging evidence indicates that TREM2 expression is markedly upregulated in pancreatic macrophages of obese subjects, where TREM2-driven macrophage activation promotes pro-inflammatory cytokine release and disrupts macrophage-islet β-cell crosstalk. Transcriptomic profiling reveals that TREM2 signaling reshapes macrophage transcriptional landscapes, enhancing pro-inflammatory phenotypes while impairing islet-supporting capacity. Notably, macrophage-specific TREM2 ablation has been shown to ameliorate pancreatic inflammation, restore islet insulin secretion, and alleviate systemic metabolic disorders in obese mice. Collectively, these findings identify TREM2 as a pivotal molecular switch governing pancreatic macrophage-mediated metabolic dysfunction in obesity, highlighting TREM2+ pancreatic macrophages as a potential therapeutic target. These findings advance the understanding of immune-metabolic crosstalk in the pancreas, laying a foundation for developing novel immunometabolic interventions.
Core Tip: Triggering receptor expressed on myeloid cells 2-expressing pancreatic macrophages represent a promising therapeutic target bridging obesity, islet inflammation, and metabolic disorders. The central theme of this review focuses on the phenotypic remodeling characteristics of macrophages in obesity, the regulatory mechanisms of triggering receptor expressed on myeloid cells 2, and its impacts on macrophage-β cell crosstalk, followed by a discussion on translational prospects and challenges.
