Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) that affects 1% to 6% of the U.S. population and is expected to rise due to increasing comorbidities including type 2 diabetes and cardiovascular disease. Recent research has identified TREM2-expressing macrophages as critical mediators at the intersection of lipid metabolism and immune response in MASH pathogenesis.
TREM2+ Macrophages: Key Players in Hepatic Homeostasis
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) has emerged as a pivotal regulator linking metabolic dysfunction to immune responses in chronic liver diseases. TREM2+ macrophages, including both lipid-associated macrophages (LAMs) and TREM2+ Kupffer cells, demonstrate remarkable functional versatility in MASH progression.
During MASH development, resident Kupffer cells participate in lipid storage but ultimately lose their self-renewal capacity, leading to cell death. Monocyte-derived macrophages recruited from the periphery can differentiate into at least two distinct populations: monocyte-derived Kupffer cells that replenish the lost resident population, or LAMs characterized by CD9 and TREM2 expression.
Spatial transcriptomics have revealed that TREM2+ macrophages localize to sites of hepatocellular damage, inflammation, and fibrosis in the steatotic liver. These specialized macrophages exhibit enhanced lipid metabolism, phagocytic activity, and secretion of anti-inflammatory mediators including IL-10 and TGF-β.
Dual Regulatory Mechanisms in Lipid Metabolism
TREM2+ macrophages demonstrate sophisticated mechanisms for managing hepatic lipid homeostasis. Studies comparing TREM2-deficient mice with wild-type littermates under high-fat diet conditions revealed that TREM2-/- mice displayed exacerbated metabolic phenotypes, including increased body and liver weight, systemic and hepatic lipid dysregulation, and histopathological evidence of liver injury.
The lipid regulatory functions of TREM2+ macrophages operate through several key mechanisms:
Enhanced Lipid Phagocytosis: TREM2 interacts with lipid-associated molecules such as apolipoprotein E (APOE) to enhance macrophage phagocytosis of cholesterol and oxidized lipids. TREM2-deficient macrophages are unable to effectively phagocytose toxic lipids released from lipotoxic hepatocytes, leading to hepatocyte apoptosis and exacerbation of liver inflammation and fibrosis.
Cholesterol Transport Regulation: TREM2 promotes cholesterol transport by activating the LXR-ABCA1/G1 axis, facilitating cholesterol efflux and preventing excessive cholesterol accumulation. This function has been validated in microglia studies, where TREM2-deficient cells showed insufficient cholesterol efflux, leading to accumulation of cholesterol esters and oxidized cholesterol esters.
Metabolic Pathway Modulation: TREM2 affects lipid peroxidation by changing metabolic pathways and reactive oxygen species production in liver macrophages after liver injury, contributing to overall hepatic metabolic homeostasis.
Immune Response Modulation and Anti-Inflammatory Functions
TREM2+ macrophages play crucial roles in maintaining hepatic immune homeostasis through multiple anti-inflammatory mechanisms. The receptor suppresses inflammation by negatively regulating the synthesis of pro-inflammatory cytokines such as TNF-α and IL-6, while inhibiting the secretion of pro-inflammatory mediators from Kupffer cells.
TLR4 Pathway Antagonism: TREM2 exerts anti-inflammatory effects by antagonizing downstream proteins associated with TLR4 signaling, including p38 mitogen-activated protein kinase (p38-MAPK) and extracellular signal-regulated kinase (ERK). By suppressing TLR4 signaling, TREM2 helps prevent excessive inflammation in response to infection or injury.
Macrophage Polarization: Activation of TREM2 signaling promotes macrophage polarization toward the anti-inflammatory M2 phenotype, which is associated with inflammation resolution and tissue repair. This polarization contributes to the release of M2-related cytokines including IL-10 and TGF-β.
Apoptotic Cell Clearance: TREM2+ macrophages facilitate the clearance of necrotic and apoptotic hepatocytes, preventing the spread of inflammatory factors and promoting tissue repair. This phagocytic function helps maintain tissue homeostasis and prevents secondary necrosis that could release additional pro-inflammatory danger signals.
Clinical Implications and Therapeutic Potential
The discovery of TREM2's dual regulatory roles has significant clinical implications for MASH diagnosis and treatment. Soluble TREM2 (sTREM2), produced through cleavage by ADAM10 or ADAM17, shows promise as a diagnostic biomarker. Studies demonstrate that increased levels of sTREM2 appear earlier than other laboratory markers of MASH in both patients and mouse models, potentially serving as a reliable noninvasive indicator for determining disease stage and progression.
Therapeutic Targeting Strategies: Several approaches for modulating TREM2 in MASH treatment are being explored:
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TREM2 Agonists: Compared with conventional broad-spectrum immunosuppressants such as CCR2/CCR5 antagonists and IL-1β blockers, targeting TREM2 offers superior safety and adaptability across different pathological stages of the disease.
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Gene Therapy: Utilizing gene editing technology to increase TREM2 expression in liver macrophages or increase the proportion of TREM2+ macrophages in the liver could provide anti-inflammatory effects and MASH reversal.
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Gut-Liver Axis Modulation: Strategies that modulate gut microbiota or reduce gut permeability could indirectly influence TREM2+ macrophage activation and function through prebiotics, probiotics, or other therapies designed to balance the gut microbiome.
Stage-Specific Considerations and Future Directions
While TREM2+ macrophages demonstrate protective functions in early MASH stages, recent research has revealed potential pro-fibrotic roles in advanced disease. In chronic or advanced stages, sustained activation of TREM2+ macrophages in an inflammatory and lipid-rich microenvironment may lead to a phenotypic shift toward pro-fibrotic functions, contributing to hepatic fibrosis through secretion of profibrotic mediators such as TGF-β and platelet-derived growth factor (PDGF).
This dual nature necessitates stage-specific therapeutic approaches. In early MASH stages, TREM2 upregulation may represent a hepatic compensatory response aimed at clearing excessive lipids and attenuating liver inflammation. However, in advanced stages, therapeutic strategies may need to balance TREM2 modulation with appropriate antifibrotic agents.
The integration of nanotechnology with TREM2 agonists could facilitate targeted delivery to liver tissue, improving the specificity and precision of TREM2 modulation while avoiding potential central nervous system side effects associated with systemic TREM2 targeting.
As approximately 122 million U.S. adults are expected to be diagnosed with MASLD by 2050, understanding TREM2's complex roles in MASH pathogenesis becomes increasingly critical. Future research focusing on tissue-specific TREM2+ macrophage subsets, precise molecular mechanisms, and stage-adapted therapeutic strategies will be essential for translating these findings into effective clinical interventions for MASH patients.
