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

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.

Key Words: Triggering receptor expressed on myeloid cells 2; Obesity; Pancreatic macrophages; Pancreatic inflammation; Immunometabolism

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.

INTRODUCTION

Obesity has become a global health burden and significantly increases the risk of metabolic diseases such as insulin resistance and type 2 diabetes[1]. The imbalance of glucose metabolism related to obesity is not caused by a single organ, but is the result of the combined effect of multiple tissues under the background of long-term overnutrition and chronic low-grade inflammation[1]. Among them, the impairment of pancreatic islet β-cell function and the formation of a local inflammatory microenvironment in the pancreas are important links in the transition from compensation to decompensation, but their immune regulatory mechanisms have not yet been fully clarified[2,3].

In the pancreatic immune microenvironment, macrophages have a numerical advantage and high plasticity, and can participate in homeostasis maintenance and inflammatory regulation through cytokines, phagocytic clearance, and direct interaction with β-cells[4]. Under the condition of obesity, the recruitment source, spatial distribution, and functional state of pancreatic macrophages are reshaped, and pro-inflammatory signals are enhanced. These changes may disrupt the homeostasis between macrophages and β-cells, thereby exacerbating β-cell stress, insulin secretion disorders, and local tissue remodeling[2,4]. Due to the significant heterogeneity of pancreatic macrophages and the difficulty of the traditional M1/M2 dichotomy framework in summarizing their diverse functional states related to obesity, identifying key molecular hubs has become a necessary prerequisite for understanding the disease course and developing intervention strategies[4].

Triggering receptor expressed on myeloid cells 2 (TREM2), as a myeloid cell membrane receptor, can regulate the activation threshold of macrophages, inflammatory transcription programs, and immune metabolic adaptation[5]. More and more evidence suggests that TREM2-related signals in the obese pancreas may drive macrophages to shift towards a state unfavorable to islet homeostasis, and are associated with the release of pro-inflammatory factors, β-cell function decline, and systemic metabolic disorders, suggesting that it has potential intervention value[3,5]. Based on these observations, this review will focus on the remodeling characteristics and functional imbalances of pancreatic macrophages in obesity, systematically sort out the signaling mechanism of TREM2 and its role in macrophage-β-cell interactions, and discuss the transformation prospects and challenges of targeting TREM2 (Figure 1).

Figure 1 Schematic diagram of TREM2-driven pancreatic macrophage activation in obesity and its metabolic consequences. Triggering receptor expressed on myeloid cells 2 (TREM2) is markedly upregulated in pancreatic macrophages during obesity, reprogramming them to a pro-inflammatory state. This TREM2-driven activation disrupts the crosstalk with islet β-cells, leading to local insulin resistance and metabolic imbalance. Crucially, as the figure depicts, genetic ablation of TREM2 reprograms macrophages to a resting (TREM2^-) phenotype. This intervention attenuates inflammation, restores β-cell function and insulin secretion, and re-establishes systemic metabolic homeostasis, validating TREM2 as a pivotal molecular switch and a promising therapeutic target. TREM2: Triggering receptor expressed on myeloid cells 2.

TISSUE-SPECIFIC CHARACTERISTICS OF PANCREATIC MACROPHAGES

Pancreatic islet macrophages are suggested to be mainly derived from primitive macrophages during embryonic development rather than blood monocytes in adulthood, and they may be sustained within islets long term through self-proliferation (Table 1)[6]. Macrophages in different anatomical locations exhibit distinct surface marker expression profiles, which are considered to reflect their functional differences. F4/80, a classic macrophage marker, is expressed by almost all pancreatic macrophages and serves as a fundamental identifier of macrophage identity[7,8]. CD206, a mannose receptor and M2 phenotypic marker, is predominantly expressed by macrophages in the acinar stroma and around ducts; these CD206+ cells tend to display an M2-like phenotype with anti-inflammatory and tissue repair functions[9]. In contrast, CD206- macrophages are primarily located in the peri-islet region and typically exhibit stronger antigen-presenting capacity and pro-inflammatory characteristics[9]. Major histocompatibility complex class II (MHC-II), a major histocompatibility complex molecule involved in antigen presentation, shows differential expression: MHC-II-high macrophages are predominantly found in the peri-islet region, possessing potent antigen-presenting ability to activate T cells, while MHC-II-low macrophages are mainly distributed in the acinar stroma, with relatively weak immune surveillance functions but still playing important roles in tissue homeostasis. Notably, pancreatic macrophages also exhibit heterogeneity within the same tissue; for example, although peri-islet macrophages express high levels of F4/80, their CD206 and MHC-II expression levels can potentially change in response to microenvironmental stimuli.

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

Dynamic balance between self-renewal and monocyte recruitment

The maintenance of pancreatic macrophage populations is proposed to result from the combination of embryonic-derived self-renewal and bone marrow-derived monocyte recruitment, with this balance being tissue-specific. Islet macrophages form early during embryonic development and possess long-term self-renewal capacity; they can be maintained for extended periods under steady-state conditions (with a long half-life) and are found to be insensitive to bone marrow-derived monocyte recruitment[10,11]. In contrast, macrophages located in the acinar stroma and around ducts are suggested to be mainly derived from circulating monocytes, characterized by a relatively short lifespan (short half-life) and requiring continuous replenishment by blood monocytes to maintain population size. Under steady-state conditions, islet macrophages primarily rely on self-renewal, while exocrine region macrophages depend on monocyte recruitment. However, during inflammation or injury (e.g., pancreatitis), this balance may be disrupted, leading to massive monocyte infiltration that replaces resident tissue macrophages or results in the inactivation of self-renewing macrophages[12].

TREM2 MACROPHAGE SIGNALING: MOLECULAR MECHANISMS

TREM2 ligand recognition and signal transduction

TREM2 can specifically recognize and bind to a variety of ligands, including apolipoproteins, complement components, and lipid molecules exposed on the surface of damaged cells[13-15]. Its extracellular immunoglobulin-like domain serves as the core functional region for ligand binding, achieving binding specificity through unique surface structural features. Specifically, the hydrophobic pocket formed by the complementarity-determining regions loops is the key site mediating its binding to proteins such as apolipoprotein E[14], while the basic region formed by arginine residues is responsible for interacting with negatively charged molecules such as C1q[14,16]. Notably, structural biology studies have confirmed that different ligand-binding sites of TREM2 overlap, suggesting potential competitive or synergistic regulatory effects between different ligands[14]. At the level of signal transduction, TREM2 lacks an intracellular signaling domain, and its functional exertion is completely dependent on forming a complex with the adaptor protein DNAX-activating protein of 12 kDa. After ligand binding, the TREM2-DNAX-activating protein of 12 kDa complex recruits and activates spleen tyrosine kinase, thereby initiating downstream pathways such as phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase[17,18]. This signal transduction process is considered the core molecular basis for macrophages to perform phagocytic functions and promote tissue repair. Meanwhile, this signaling system is subject to multi-level negative regulation, for instance, through inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 2, which can antagonize TREM2 activation signals by recruiting phosphatases via its intracellular immunoreceptor tyrosine-based inhibitory motif[19]. These ligand recognition and signaling events provide the foundation for subsequent metabolic and functional events.

TREM2-driven macrophage functional reprogramming

TREM2 activation is thought to reshape the transcriptomic and metabolic status of macrophages, thereby modulating their functional phenotypes; however, current understanding is derived largely from studies in other tissues rather than the pancreas. At the metabolic level, TREM2 has been reported to induce a switch from oxidative phosphorylation to glycolysis in certain contexts—for example, in the tumor microenvironment, it promotes an immunosuppressive phenotype in tumor-associated macrophages by activating pyruvate kinase M2-dependent glycolysis[20]—whereas in neuroprotection, it enhances oxidative phosphorylation in microglia via insulin-like growth factor 1[21], illustrating the context-dependent nature of TREM2-driven metabolic remodeling. Additional metabolic adaptations have been observed in TREM2-positive macrophages, such as inhibiting SLC25A53 to interrupt the tricarboxylic acid cycle and accumulate itaconate during cardiac repair[22]. In terms of functional regulation, studies suggest that TREM2 may selectively enhance phagocytic clearance while modulating inflammatory responses—a phenomenon referred to as phagocytosis-inflammation decoupling. For instance, synaptic phagocytosis induced by repeated lipopolysaccharide stimulation has been shown to depend on TREM2-mediated reprogramming, while inflammatory tolerance appears independent of it, suggesting that TREM2-positive cells might enhance clearance function without necessarily exacerbating inflammatory responses[23]; similar observations have been made in the context of TREM2-dependent Aβ clearance in Alzheimer’s disease models[23,24]. It should be emphasized, however, that direct evidence for TREM2-driven metabolic reprogramming (particularly the oxidative phosphorylation-glycolysis switch) and for phagocytosis-inflammation decoupling in resident pancreatic macrophages is currently lacking, as existing data predominantly originate from microglia, cardiac macrophages, and tumor-associated macrophages[20-24]. Therefore, while these observations raise the possibility that similar mechanisms may operate in the pancreas, this remains a hypothesis requiring direct validation in pancreatic-specific models.

Disease and tissue environment dependence of TREM2 function

The functional phenotype of TREM2 appears to be modulated by the surrounding pathophysiological microenvironment, and findings from other tissues should be extrapolated to the pancreas only with caution. In acute central nervous system injury, TREM2 has been associated with driving microglia toward a protective phagocytic phenotype, with molecular signatures (such as purinergic receptor P2Y12 and apolipoprotein E expression) adapting to different injury types[25]. However, pancreatic macrophages differ in ontogeny (originating from embryonic or monocyte-derived lineages) and reside in a microenvironment characterized by high digestive enzyme exposure and unique islet circulation; their TREM2 regulatory network may therefore differ from that of microglia, and whether analogous injury-dependent phenotypic shifts occur in the pancreas remains to be directly investigated. In chronic cardiovascular diseases, TREM2 has been reported to exhibit stage-dependent functions—promoting plaque progression in early atherosclerosis but enhancing stability in advanced stages, while exerting protective effects in myocardial infarction[26]. Nevertheless, given that pancreatic diseases such as pancreatitis and pancreatic ductal adenocarcinoma involve distinct pathological processes, TREM2 function in these contexts may be shaped by factors not present in cardiovascular tissues, and direct evidence from pancreatic disease models is currently lacking. In the tumor microenvironment, TREM2-positive macrophages display complex dual potentials, with their functional orientation regulated by specific immune contexts such as human papillomavirus infection[27]; in pancreatic ductal adenocarcinoma, the dense desmoplastic stroma and immunosuppressive milieu might modulate TREM2 function in ways distinct from other tumor types. This high environmental dependence supports the hypothesis that TREM2 may exhibit unique regulatory features in the pancreas, highlighting the need for direct investigation using pancreatic disease models.

Summary and inference

The function of TREM2 is markedly tissue- and disease context-dependent. In central nervous system injury models, TREM2⁺ microglia are specifically induced to exert neuroprotective effects by phagocytosing and clearing degenerative debris[25]. In cardiovascular diseases such as atherosclerosis, its role exhibits stage dependency, shifting from promoting lesion progression in the early stage to enhancing plaque stability in the advanced stage[26]. In the human papillomavirus-positive tumor microenvironment, TREM2⁺ macrophages further display a complex duality of immune suppression and inflammatory activation[27]. These observations suggest that, as a key regulator of myeloid cells, the functional output of TREM2 is highly dependent on the specific signaling network constituted by the local microenvironment. Based on this consistent pattern of context dependence, it is plausible to hypothesize that in pancreatic cancer—a pathological setting characterized by a unique fibrotic and immunosuppressive microenvironment—TREM2 may drive distinct functional programs. Existing studies provide correlative evidence consistent with this possibility: In pancreatic cancer, the expression of TREM2 has been associated with specific molecular subtypes and immune signatures[28], and is closely associated with the enrichment of M2-type tumor-associated macrophages and the formation of an immunosuppressive microenvironment[28,29]. Functionally, TREM2 has been linked to the proliferation and migration of pancreatic cancer cells, and to phosphoinositide 3-kinase pathway-mediated drug resistance[28]. This alteration is not confined to the local tumor site, but also manifests as the systemic upregulation of TREM2 and its related genes in peripheral blood monocytes of patients[29]. Collectively, these lines of evidence raise the possibility that in the unique microenvironment of pancreatic cancer, TREM2 may contribute to immune suppression and tumor progression. Its mode of action in this setting may differ from its well-characterized roles in the nervous or cardiovascular system, consistent with the tissue specificity of TREM2 functions.

OBESITY-ASSOCIATED ACCUMULATION AND DYSFUNCTION OF PANCREATIC MACROPHAGES

Time-dependent infiltration in high-fat diet models

Under physiological conditions, the pancreas contains tissue-resident macrophages with diverse origins and functions, and islet macrophages constitute a major immune population within islets. In the exocrine pancreas, F4/80^hi macrophages can be stratified by developmental markers [e.g., T-cell immunoglobulin and mucin domain-containing protein 4 (Tim-4)] and MHC-II expression, highlighting baseline heterogeneity in their location, ontogeny, and immunophenotype[30]. In diet-induced obesity/high-fat diet (HFD) models, this heterogeneity is reported to shift, including an increased proportion of Tim-4^-MHCII⁺ macrophages in the exocrine region with C-C motif chemokine receptor 2-dependent monocyte contribution[30]. By contrast, the age-associated replacement of islet-resident macrophages by bone marrow-derived cells appears relatively less dependent on the canonical C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis[30]. Together, these observations suggest that inflammatory pressures and recruitment dynamics differ across pancreatic microcompartments during HFD exposure.

Rather than occurring abruptly, immune changes in the islet environment typically evolve with the duration of HFD feeding. In murine HFD models, islet inflammation has been associated with the expansion/activation of islet macrophages, and it emerges alongside β-cell dysfunction[31]. Mechanistic studies further suggest that HFD can drive local functional remodeling of islet-associated macrophages (IAMs) beyond a strict polarization framework[32]. For example, enhanced Axl/Mertk-linked efferocytosis programs and altered transforming growth factor-beta (TGF-β) receptor signaling have been linked to impaired glucose-stimulated insulin secretion (GSIS) and β-cell stress in prediabetic states[33]. This functional remodeling feature of IAMs is consistent with the overall phenotypic changes of pancreatic macrophages; accordingly, time-dependent infiltration should be interpreted as both quantitative accumulation and qualitative state transitions of pancreatic macrophages.

Obesity is also frequently accompanied by pancreatic fat accumulation, which may provide lipid substrates and damage-associated signals that sustain innate immune activation. Recent reviews link pancreatic fat to metabolic syndrome, dysglycaemia, and type 2 diabetes, and propose its potential connections to pancreatitis risk and endocrine dysfunction[34,35]. These clinical-pathological observations are consistent with—but do not by themselves prove—a model in which fat deposition, tissue stress signaling, and immune remodeling co-evolve during prolonged HFD exposure.

Metabolic activation: From homeostatic support to pro-inflammatory drift

In homeostasis, islet-resident macrophages contribute to immune surveillance and tissue maintenance. They can support β-cell and islet vascular function by producing trophic factors [e.g., platelet-derived growth factor (PDGF) and vascular endothelial growth factor] and participating in local immune regulation[33]. In the setting of obesity/HFD, nutrient excess and cell stress can amplify macrophage inflammatory outputs, including interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), which correlate with reduced GSIS and intensified local inflammation within islets[36].

Importantly, these state shifts often form a continuum and are difficult to capture using the M1/M2 binary classification. In adipose tissue, obesity induces multiple macrophage states linked to lipid handling and metabolic reprogramming (e.g., lipid-associated and metabolically activated macrophages), reflecting a tight coupling between nutrient cues and immune programs[37]. Emerging evidence suggests that IAMs exhibit analogous remodeling: Under basal conditions, IAMs maintain mixed glycolytic and oxidative metabolic programs and can modulate GSIS, whereas after HFD exposure, their metabolic/epigenetic programs shift alongside increased Axl/Mertk-mediated efferocytosis and altered TGF-β signaling, which coincides with impaired GSIS in prediabetes[33].

Lipid-sensing receptors may further calibrate macrophage responses to lipid load and damage-associated molecular patterns during metabolic activation. TREM-2, in particular, has been linked to both tissue injury responses and lipid metabolism, and TREM-2⁺ resident macrophages correlate with lipid processing capacity, inflammatory tone, and metabolic homeostasis in several metabolic tissues[38]. In the obese pancreas, it therefore remains a plausible—but still developing—hypothesis that TREM-2-related pathways help set activation thresholds for IAMs, potentially tipping the balance between debris clearance/tissue repair and chronic pro-inflammatory output.

Association with obesity-related pancreatitis and islet fibrosis

Over the past several years, fatty pancreas has been proposed as a contributor to a broader spectrum of pancreatic disorders. Reviews link pancreatic fat deposition to abnormal glucose metabolism and suggest that chronic lipid accumulation may predispose the pancreas to structural injury (including pancreatitis), thereby secondarily impairing insulin secretion[34,35]. Within this framework, obesity-related pancreatitis can be viewed as an increased susceptibility to injury stimuli and a tendency toward persistent inflammation and fibrotic remodeling under metabolic stress.

Macrophages are potential drivers of this inflammation-fibrosis coupling. They can be activated by lipotoxic metabolites, damage-associated molecular patterns released by dying cells, and local paracrine signals; in turn, they can shape stromal responses via cytokines and growth factors. In human pancreatic inflammatory settings, IL-6 signaling from macrophages and pancreatic stellate cells has been implicated in stellate cell activation and collagen I production through the TGF-β1/Smad axis[39]. Although not obesity-specific, this pathway provides a mechanistic template that can be tested in obesity-associated pancreatic injury. Islet dysfunction may also be influenced indirectly by fibrosis in the surrounding pancreatic tissue. Excess extracellular matrix deposition can alter islet perfusion, tissue mechanics, and immune-cell trafficking, potentially exacerbating β-cell stress. Together with reports that HFD enhances TGF-β-related programs in IAMs and correlates with impaired insulin secretion[32], these data support a working model in which macrophage reprogramming and fibrotic remodeling may reinforce each other (inflammation ↔ fibrosis), contributing to progressive β-cell failure. Direct causal testing in pancreas-specific models remains needed.

Limitations of the M1/M2 binary classification

The M1/M2 dichotomy remains a convenient shorthand, but it is increasingly insufficient for the study of metabolic diseases. In adipose tissue, single-cell multi-omics studies identify multiple macrophage states spanning lipid processing, phagocytosis, antigen presentation, and cytokine programs beyond the M1/M2 classification[37]. Pancreatic macrophages show comparable complexity: Exocrine macrophages can be stratified by Tim-4 and MHC-II expression, and their proportions shift with aging and obesity[30], while islet macrophage replenishment kinetics appear distinct and are not fully explained by classical chemokine recruitment pathways[31]. Thus, more granular descriptors that integrate origin, location, and functional state are needed to interpret obesity-associated pancreatic inflammation. Functionally, IAMs operate across a range of states rather than fixed M1 or M2 endpoints. Under homeostasis, they balance glycolysis and oxidative phosphorylation and can fine-tune insulin secretion via metabolic-epigenetic programs; after HFD exposure, increased efferocytosis and altered TGFβ signaling correlate with defective GSIS[32]. Consequently, describing obesity-related pancreatic macrophages simply as more M1-like or less M2-like may obscure key determinants such as the saturation of lipid-handling capacity, the uncoupling of clearance from inflammatory resolution, and shifts in macrophage-β-cell communication from supportive to injurious.

TREM2+ MACROPHAGES IN THE OBESE PANCREAS: EVIDENCE AND MECHANISMS

The expansion and functional reprogramming of macrophages are well-documented features of pancreatic remodeling in obesity. Recent evidence implicates TREM2 as a pivotal molecular switch that links metabolic stress to macrophage heterogeneity within this niche. Its expression is induced under obesogenic conditions, positioning TREM2 at the nexus of metabolic signaling, immune response, and tissue remodeling. Convergent findings from multiple studies over recent years indicate that TREM2 marks an expanded macrophage subpopulation in the obese pancreas, which appears to exacerbate a β-cell stress-fibrosis vicious cycle through metabolic reprogramming and paracrine signaling.

Evidence for upregulation of TREM2 in obese pancreatic macrophages

Transcriptional profiling suggests that TREM2⁺ pancreatic macrophages adopt a state of metabolic-inflammatory dual activation. On the one hand, these cells show significant enrichment in pathways related to phagosome, lysosome, and lipid metabolism, equipping them for efficient clearance of cellular debris and lipid droplets. On the other hand, they sustain the secretion of pro-inflammatory cytokines such as IL-1β and TNF-α, alongside certain atypical anti-inflammatory factors[40]. Functional metabolic analysis (e.g., Seahorse) corroborated this shift, showing a 1.8-fold increase in basal glycolysis (extracellular acidification rate) and a concurrent 32% decrease in oxidative phosphorylation (oxygen consumption rate) in TREM2+ macrophages compared to their TREM2- counterparts, indicative of a metabolic reprogramming akin to the Warburg effect[40]. This metabolic adaptation may support adenosine triphosphate (ATP) production in the relatively hypoxic and lactate-rich islet microenvironment while stabilizing the translation of pro-inflammatory mediators via the mechanistic target of rapamycin-signal transducer and activator of transcription 3 axis[40]. Notably, elevated mRNA and protein levels of pro-fibrotic factors like TGF-β1 and platelet-derived growth factor C were also observed in TREM2+ cells, implying a potential role in actively driving collagen deposition beyond sustaining inflammation[41]. Collectively, these features position TREM2+ macrophages in a transitional state between repair and destruction: They may contribute to waste clearance acutely, but their persistent activation likely promotes the establishment of a pro-fibrotic microenvironment.

Functional phenotype of TREM2⁺ macrophages

Transcriptional characterization suggests that TREM2⁺ pancreatic macrophages are in a state of “metabolic-inflammatory dual activation”: On the one hand, they are significantly enriched in phagosomes, lysosomes, and lipid metabolic pathways, which endow them with the ability to efficiently remove dead cells and lipid droplets; on the other hand, they continue to secrete low levels of IL-1β, TNF-α, and atypical M2-type anti-inflammatory factors[1,3]. Functional metabolic analysis (Seahorse) confirmed a 1.8-fold increase in basal glycolysis (extracellular acidification rate) and a 32% decrease in oxidative phosphorylation (oxygen consumption rate) in TREM2⁺ macrophages compared to TREM2^- siblings, consistent with Warburg-like reprogramming[40]. This metabolic shift enabled the maintenance of ATP supply in the low-oxygen, high-lactate environment of pancreatic islets, while stabilizing pro-inflammatory factor translation via the mechanistic target of rapamycin-signal transducer and activator of transcription 3 axis[40]. Notably, the mRNA and protein levels of TGF-β1 and platelet-derived growth factor C were synchronously elevated in TREM2⁺ cells, suggesting that they may actively drive collagen deposition in addition to inflammatory maintenance[41]. Thus, TREM2⁺ macrophages represent a transitional state between “repair-destruction”: They contribute to the removal of metabolic waste in the short term, while their long-term presence promotes the formation of a fibrotic microenvironment.

TREM2-mediated macrophage-β-cell crosstalk

Spatial transcriptomic (Visium) data indicate that regions enriched for TREM2 signaling are located within 50 μm of the islet β-cell core, providing an anatomical basis for paracrine interactions[41]. In vitro transwell co-culture experiments demonstrated that supernatant from TREM2+ macrophages reduced GSIS from MIN6 β-cells by 42% within 24 hours. This impairment was largely restored (70%) by an IL-1 receptor antagonist, identifying IL-1β as a major functional effector[40]. Furthermore, TREM2 signaling itself modulates the sensitivity of macrophages to damage-associated molecular patterns (DAMPs). Pretreatment with an agonistic anti-TREM2 antibody potentiated subsequent ATP-induced IL-1β release by 2.3-fold, whereas macrophages lacking TREM2 exhibited a markedly attenuated response to apoptotic β-cell debris[40]. These observations support a model of a pathogenic positive feedback loop: Β-cell stress results in the release of DAMPs, which are sensed by TREM2 on macrophages, leading to amplified pro-inflammatory output. Cytokines like IL-1β then further inhibit β-cell function and promote apoptosis, resulting in the release of more DAMPs. In vivo validation in Trem^2-/- mice fed an HFD showed attenuation of this cycle, manifested as a 35% reduction in islet collagen area, a 40% decrease in β-cell apoptosis, and significantly improved systemic glucose tolerance[40,42]. Together, this complementary in vivo and ex vivo evidence underscores a central role for TREM2 in amplifying metabolic-immune cross-talk within the obese pancreas and provides a rationale for considering TREM2 blockade as a potential therapeutic strategy.

CLINICAL STRATEGIES

In parallel with immune-targeted strategies, lifestyle management remains foundational in obesity care. Exercise science studies suggest that aerobic training paired with dietary modification, as well as high-intensity interval training-based protocols, can positively influence physiological indicators and functional performance, providing a practical adjunct layer that may complement emerging immunometabolic interventions. In clinical strategies, genetic interventions targeting TREM2 have been explored through a range of mechanistic strategies in preclinical settings. Table 2 summarizes the key approaches, delivery platforms, and corresponding therapeutic outcomes[43-48].

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.

CONCLUSION

Obesity can shape an abnormal immune-metabolic microenvironment characterized by chronic low-grade inflammation, fat deposition, and tissue remodeling in the local pancreas. The expansion of pancreatic macrophages, source supplementation, and functional state drift are the key links in the transformation from compensation to decompensation. Pancreatic macrophages are highly heterogeneous in spatial distribution and phenotype. This heterogeneity is further magnified in an obese state, promoting the intensification of peri-islet inflammation and the progression of fibrosis, and weakening the secretion capacity of β cells through paracrine/cellular interactions, ultimately accelerating the decline of islet function. In the above process, TREM2 is manifested as the core node connecting lipid/damage signals and macrophage reprogramming: It prompts macrophages to enter a state that combines lipid processing and inflammatory/pro-fibrotic output, strengthening the positive feedback loop of inflammation-fibrosis-β-cell damage, thus becoming a potential target for immune metabolic intervention. However, TREM2 may exhibit bidirectional effects in different organs and at different stages of the disease course, suggesting that in the future, it is necessary to rely on single-cell and spatial omics to identify key subpopulations and action windows, develop pancreatic specific delivery and monitorable biomarkers, and verify their causal associations in human samples and longitudinal cohorts, laying the foundation for precise, long-term, and safe combination treatment strategies.