Triggering receptor expressed on myeloid cells 2-driven pancreatic macrophage crosstalk: Key regulator of obesity pathophysiology and metabolic dysregulation

Table 1 Anatomical distribution: Peri-islet, acinar stroma, and ductal regions

Category	Core content	Ref.
Peri-islet region	This subpopulation is mainly located around and within pancreatic islets; macrophages in this region typically possess higher activity and antigen-presenting capacity, participating in islet immune surveillance and the regulation of insulin secretion	Calderon et al[7], 2015
Acinar stroma	Situated in the interstitial tissue between exocrine acini; this subpopulation of macrophages is relatively abundant, mainly involved in tissue homeostasis maintenance and injury repair, displaying stronger phagocytic ability and tissue repair functions	Unanue et al[8], 2016
Ductal region	Located around pancreatic ducts, particularly the larger ones; these macrophages may be associated with ductal secretory and defensive functions, and are closely linked to the occurrence and development of duct-related diseases	Calderon et al[7], 2015

Table 2 Clinical strategies

Strategy category	Detailed description	Ref.
Preclinical evidence of the TREM2 gene intervention	TREM2 regulates pancreatic macrophage function in obesity; gene knockout/overexpression are core approaches with significant preclinical regulatory effects, supported by peer-reviewed studies confirming TREM2 as a key modulator of pancreatic immune homeostasis in metabolic disorders	Fabre et al[43], 2023
TREM2 knockout (Cre-LoxP system)	In HFD-induced obese mice, pancreatic macrophage-specific TREM2 knockout downregulates IL-6/TNF-α, reduces islet fibrosis by approximately 40%, and restores β-cell insulin secretion, consistent with peer-reviewed findings that TREM2 deletion alleviates pancreatic inflammatory injury	Fabre et al[43], 2023; Liebold et al[44], 2023
AAV-mediated TREM2 overexpression	Pancreatic tissue-specific: Exacerbates acinar cell lipotoxic injury (acinar macrophages) and alleviates islet inflammation (islet macrophages via NF-κB inhibition), supported by peer-reviewed research on AAV-mediated tissue-specific gene regulation in pancreatic diseases	Fabre et al[43], 2023
CRISPR-Cas9-mediated epigenetic editing	Downregulates abnormal TREM2 overexpression in obese pancreas, sustaining improved glucose tolerance in mice for > 12 weeks; peer-reviewed studies validate CRISPR-Cas9 as a reliable tool for pancreatic gene epigenetic modification	Liebold et al[44], 2023
RNA interference (LNP-siRNA -mediated)	Targets pancreatic macrophages, silences TREM2 mRNA, reduces TREM2+ macrophages, and improves insulin sensitivity in obese mice, corroborated by peer-reviewed evidence of LNP-siRNA targeting efficacy in pancreatic immune cells	Fabre et al[43], 2023; Lopez-Pascual et al[45], 2025
Key challenges in clinical translation	(1) Insufficient gene delivery tissue specificity (off-target risks); and (2) Unverified safety/Long-term stability (off-target editing, AAV-induced immune responses); these challenges are widely recognized in peer-reviewed translational studies
Feasibility of clinical translation	Supported by Cre-LoxP specificity, clinically approved LNP platforms, and CRISPR-Cas9 Long-term efficacy, with peer-reviewed studies confirming LNP and CRISPR-Cas9 translational potential in metabolic and pancreatic diseases	Fabre et al[43], 2023
Future directions of TREM2 gene intervention	(1) Subgroup-targeted intervention; (2) Combined gene technologies; (3) Non-invasive delivery; and (4) Clinical trials for safety/efficacy verification; all directions are proposed in peer-reviewed studies focusing on TREM2 and pancreatic disease translation
Neuromodulation (EA as adjunct)	EA (ST25) alleviates islet inflammation/preserves β-cell function via TRPV1+-CGRP pathway; complements TREM2-targeted therapy, supported by peer-reviewed research on EA’s neuro-immune regulatory role in pancreatic and metabolic disorders	Liu et al[46], 2025; Lam et al[47], 2024
Limitations of EA	Lack of standardized parameters, interindividual response variability, and insufficient long-term safety evidence are consistently reported in peer-reviewed EA translational studies	Lam et al[47], 2024
Multimodal therapeutic strategy	Combine optimized EA with TREM2+ macrophage modulation; future studies to validate synergy, define parameters, and identify biomarkers, a direction supported by peer-reviewed evidence of combined neuromodulation and immune targeting in metabolic disorders	Lam et al[47], 2024; Wang et al[48], 2025

TREM2: Triggering receptor expressed on myeloid cells 2; IL: Interleukin; TNF-α: Tumor necrosis factor-α; HFD: High-fat diet; NF-κB: Nuclear factor kappa-B; AAV: Adeno-associated virus; CRISPR-Cas9: Clustered regularly interspaced short palindromic repeats-associated protein 9; LNP-siRNA: Lipid nanoparticle-small interfering RNA; EA (ST25): Electroacupuncture at ST25; TRPV1⁺-CGRP: Transient receptor potential vanilloid 1 positive neurons-calcitonin gene-related peptide.