Role Of TREM2 Research Articles

Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

TREMendous microglial effects on neurons

TREM2 is exclusively expressed by microglia in the brain and is strongly associated with Alzheimer's disease risk. In this issue of Immunity, Tagliatti etal. shed light on a novel role of TREM2 in shaping neuronal bioenergetics during development.

Inflammation and Brain Structure in Alzheimer's Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study.

Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = -9.088, p-value = 1.02 × 10-19; sTREM2: z-score = -7.495, p-value = 6.61 × 10-14). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = -4.238, p-value = 2.26 × 10-5) and pole temporal (z-score = -4.549, p-value = 5.40 × 10-6). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD.

Immune profiling of murine cardiac leukocytes identifies triggering receptor expressed on myeloid cells 2 as a novel mediator of hypertensive heart failure.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling. Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure. Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.

TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo.

The role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.

TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation

BackgroundTREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer’s disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear.MethodsThe expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer’s Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions.ResultsThree distinct TREM2 transcripts, namely ENST00000373113 (TREM2230), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2222) and ENST00000338469 (TREM2219), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin.ConclusionsTREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.

Pathways linking aging and atheroprotection in Mif-deficient atherosclerotic mice.

Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age-dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe-/- mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. Mif-deficient mice exhibited reduced atherosclerotic lesions in the 30/24- and 42/36-week-old groups, but atheroprotection, which in the applied Apoe-/- model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42- and 52/6-week-old groups. This suggested that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age-related phenotypes. We found that Mif deficiency promotes lesional macrophage and T-cell counts in younger but not aged mice, with subgroup analysis pointing toward a role for Trem2+ macrophages. The transcriptomic analysis identified pronounced MIF- and aging-dependent changes in pathways predominantly related to lipid synthesis and metabolism, lipid storage, and brown fat cell differentiation, as well as immunity, and atherosclerosis-relevant enriched genes such as Plin1, Ldlr, Cpne7, or Il34, hinting toward effects on lesional lipids, foamy macrophages, and immune cells. Moreover, Mif-deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm'aging are either not downregulated or even upregulated in Mif-deficient aged mice compared with the corresponding younger ones. Lastly, Mif deficiency favored formation of lymphocyte-rich peri-adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif-gene deficiency in atherogenic Apoe-/- mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm'aging and MIF pathways in atherosclerosis and may have implications for translational MIF-directed strategies.

Combined single-cell RNA-seq and bulk RNA-seq to analyze the expression and role of TREM2 in bladder cancer.

Currently, reprogramming macrophages has emerged as one of the most promising therapeutic strategies in cancer treatment. Many studies have found that myeloid trigger receptor-2 (TREM2) is mainly expressed on tumor-associated macrophages (TAMs), and targeting TREM2 promotes reprogramming of TAMs and enhances the immunotherapeutic effect of tumors. Nevertheless, the expression and role of TREM2 in different tumor tissues are still controversial. For example, some studies have found that TREM2 can also be expressed on tumor cells and exert pro-tumor functions. It has also been found that TREM2 expression can inhibit tumorigenesis and progression. In fact, there are still no relevant studies on the expression and role of TREM2 in bladder cancer (BLCA). Therefore, the present study combined single-cell RNA-seq and bulk RNA-seq to analyze the expression, role, and molecular mechanism of TREM2 in BLCA. We found that TREM2 was predominantly expressed on TAMs in BLCA, followed by tumor epithelial cells. This finding could be useful for further exploration of the role and mechanism of TREM2. Moreover, TREM2 expression correlates with clinical progression and immunotherapy efficacy, and is an important predictor of prognosis for BLCA patients. Not only that, we also found that TREM2 may exert its effects by promoting epithelial mesenchymal transition (EMT) and T-cell exhaustion. TREM2+ TAMs may play an important pro-tumor role through PTN, ANGPTL, and VISFATIN pathways. In conclusion, our study found that TREM2 is not only a predictor of BLCA prognosis, but also a potential therapeutic target for BLCA.

IMMU-35. TREM2 RESTRAINS ANTI-TUMOR CELL ACTIVITY OF MYELOID CELLS IN GLIOBLASTOMA

Abstract Tumor-associated myeloid cell populations occupy a major part of the glioblastoma (GBM) tumor microenvironment (TME). The prevailing view is that myeloid cells in the TME are immunosuppressive and promote GBM tumor progression. However, myeloid cells have the functional plasticity to either restrict or support tumor cell growth. TREM2 has been shown to alter the myeloid cell landscape in cancers arising in the body and plays important roles in brain microglial function in neurodegenerative diseases. But the role of TREM2 in the GBM TME and specifically in myeloid cell function has not been examined. Here we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors, and that high TREM2 expression is associated with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity in vitro using patient-derived glioblastoma stem cells and mouse glioblastoma cells. Accordingly, we found TREM2 in myeloid cells restricts proinflammatory polarization in both LPS-induced innate and IFNγ-induced adaptive immunity in vitro, mainly through the inhibition of NFκB and MAPK p38 signaling pathways. Orthotopic injection of mouse glioblastoma cells into TREM2 knockout mice increased animal survival compared to littermate wildtype mice. In addition, co-implantation of TREM2 knockdown macrophages or microglia with mouse glioblastoma cells in brains of immunocompetent mice increased animal survival compared to co-implantation of control myeloid cells or injection of tumor cells alone, suggesting an important role for TREM2 in myeloid cells in GBM growth in vivo. Together, these data indicate that TREM2 operates by restricting the anti-tumor and proinflammatory function of myeloid cells in GBM and that inhibition of the TREM2 pathway may represent a potential therapeutic strategy for these patients.

TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway

BackgroundMicroglia, the innate immune cells in the central nervous system, play an essential role in brain homeostasis, neuroinflammation and brain infections. Dysregulated microglia, on the other hand, are associated with neurodegenerative diseases, yet the mechanisms underlying pro-inflammatory gene expression in microglia are incompletely understood.MethodsWe investigated the role of the actin-associated protein tropomyosin 1 (TPM1) in regulating pro-inflammatory phenotype of microglia in the retina by using a combination of cell culture, immunocytochemistry, Western blot, qPCR, TUNEL, RNA sequencing and electroretinogram analysis. TREM2−/− mice were used to investigate whether TPM1 regulated pro-inflammatory responses downstream of TREM2. To conditionally deplete microglia, we backcrossed CX3CR1CreER mice with Rosa26iDTR mice to generate CX3CR1CreER:Rosa26iDTR mice.ResultsWe revealed a vital role for TPM1 in regulating pro-inflammatory phenotype of microglia. We found that TPM1 drove LPS-induced inflammation and neuronal death in the retina via the PKA/CREB pathway. TPM1 knockdown ameliorated LPS-induced inflammation in WT retinas yet exaggerated the inflammation in TREM2−/− retinas. RNA sequencing revealed that genes associated with M1 microglia and A1 astrocytes were significantly downregulated in LPS-treated WT retinas but upregulated in LPS-treated TREM2−/− retinas after TPM1 knockdown. Mechanistically, we demonstrated that CREB activated by TPM1 knockdown mediated anti-inflammatory genes in LPS-treated WT retinas but pro-inflammatory genes in LPS-treated TREM2−/− retinas, suggesting a novel role for TREM2 as a brake on TPM1-mediated inflammation. Furthermore, we identified that TPM1 regulated inflammation downstream of TREM2 and in a microglia-dependent manner.ConclusionsWe demonstrate that TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Our findings suggest that TPM1 could be a potential target for therapeutic intervention in brain diseases.

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

Simple SummaryTriggering receptor expressed on myeloid cells 2 (TREM2) is an appealing candidate for immunotherapy. However, results regarding its role in multiple cancers are rare or even contradictory. We showed that TREM2 expression in immune cells, among which were macrophages in peripheral blood mononuclear cells and tumor-associated macrophages, was associated with advanced tumor stages and reduced survival rates in oral squamous cell carcinoma (OSCC) patients. Our findings implicate that TREM2 could serve as an effective target for prognostic and therapeutic approaches in OSCC patients. Anti-TREM2 immunotherapy might greatly improve patients’ prognosis. High levels of sTREM2 were associated with advanced UICC stages, indicating that sTREM2 might be a biomarker in OSCC patients.Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2+ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearman’s rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089–5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021–4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patients’ prognosis.

PCL22-187: Functional Role of TREM2 in NASH and HCC Development

PCL22-187: Functional Role of TREM2 in NASH and HCC Development

Functional characterization of hiPSCs‐derived glial cells and neurons from patients harboring a TREM2 loss of function mutation

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized by bone cysts and early‐onset dementia, Nasu‐Hakola disease (NHD). However, despite intense investigation, the role of TREM2 in NHD pathogenesis remains poorly understood.MethodHere, we investigated the mechanisms by which a homozygous stop‐gain TREM2 variant (Q33X), which leads to a truncated TREM2 transcript, contributes to disease pathology in NHD. Human induced pluripotent stem cells (hiPSCs)‐derived microglia (iMGLs), neurons and astrocytes were obtained from two siblings homozygous for the TREM2 Q33X mutation and one non‐carrier sibling.ResultTranscriptomic analysis and biochemical assays revealed that iMGLs from NHD patients display decreased activation, reduced lipid droplet content and defects in lysosomal function compared to related and unrelated controls. These in vitro findings were validated in brain tissues from NHD patients carrying loss of function TREM2 mutations. Strikingly, we observed defects beyond iMGLs. iPSCs‐derived neurons and astrocytes from NHD siblings displayed downregulation of pathways involved in synaptic activation, neuronal development and interferon response compared to the unaffected sibling. These pathways were also observed to be similarly altered in NHD brains. This could be due to the presence of low levels of mutant TREM2 transcripts in iPSC and neural progenitor cells, which may initiate a cascade of events that drives cellular dysfunction beyond microglia.ConclusionThese finding open a new scenario on TREM2 function and reveal that NHD is a complex pathology affecting glial cells and neurons at multiple levels.

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson's Disease.

Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2.

Liver disease accounts for millions of deaths worldwide annually being a major cause of global morbidity. Hepatotoxic insults elicit a multilayered response involving tissue damage, inflammation, scar formation, and tissue regeneration. Liver cell populations act coordinately to maintain tissue homeostasis and providing a barrier to external aggressors. However, upon hepatic damage, this tight regulation is disrupted, leading to liver pathology which spans from simple steatosis to cirrhosis. Inflammation is a hallmark of liver pathology, where macrophages and endothelial cells are pivotal players in promoting and sustaining disease progression. Understanding the drivers and mediators of these interactions will provide valuable information on what may contribute to liver resilience against disease. Here, we summarize the current knowledge on the role of macrophages and liver sinusoidal endothelial cells (LSEC) in homeostasis and liver pathology. Moreover, we discuss the expanding body of evidence on cell-to-cell communication between these two cell compartments and present triggering receptor expressed on myeloid cells-2 (Trem-2) as a plausible mediator of this cellular interlink. This review consolidates relevant knowledge that might be useful to guide the pursue of successful therapeutic targets and pharmacological strategies for controlling liver pathogenesis.

Activity and TREM2‐dependent phagocytic cup formation by microglia in the mouse cortex

AbstractBackgroundMicroglia are the main innate immune cells capable of engulfing dead cells and cellular debris in the brain. Trem2 receptor is expressed in microglia and plays an important role in phagocytosis. This receptor has been linked to Alzheimer’s disease and involved in the uptake of amyloid plaques by microglia. However, how microglia engulf dead cells and the role of Trem2 in this process remain unclear.MethodWe used two‐photon microscopy to image microglia engulfing of dead cells in the primary motor cortex of Cx3cr1 gfp/+ mice, Cx3cr1gfp/+:Trem2‐/‐ mice, Cx3cr1gfp/+:Trem2R47H/+ mice, and ThyGCaMP6 mice. These mice were placed on a custom made, free‐floating treadmill and subjected to five motor‐running sessions over one hour. Electron microscopy was used to determine the ultrastructure of microglial phagocytic cups engulfing dead cells. We manipulated neuronal activity by using AAV viral infection to express ChR2 in thalamic neurons or by administrating MK‐801 or muscimol in the motor cortex.ResultOur time‐lapse imaging data show that microglial processes form phagocytic cups to engulf dead cells within tens of minutes in the motor cortex during running. Ultrastructural examination of phagocytic cups confirmed the engulfment of dead cell body by microglial processes as revealed by live imaging. Pharmacological inhibition of neuronal activity was sufficient to prevent running‐dependent phagocytic cup formation. On the other hand, optogenetic stimulation of thalamocortical projections induced the formation of microglial phagocytic cups. In Trem2‐deficient mice and Trem2 R47H mice, running‐dependent phagocytic cup formation was reduced as compared to wild type controls. There was an increase of propidium iodide (PI)‐positive cell bodies in Trem2 deficient/haplodeficient mice comparted to the control mice.ConclusionThese findings reveal that the formation of phagocytic cups by microglia is dependent on neuronal activity and the Trem2 receptor in the mouse cortex. They also suggest that the lack of dead‐cell clearance mediated by microglia might play a role in the pathogenesis of Alzheimer’s disease.

Diesel exhaust impairs TREM2 to dysregulate neuroinflammation

BackgroundAir pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation.MethodsWYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2−/−, PHOX+/+, and PHOX−/−).ResultsRats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2−/− mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation.ConclusionsCollectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.

Myeloid Cells TREM Down Anti-tumor Responses

In this issue of Cell, Molgora etal. and Katzenelenbogen, Sheban, Yalin, etal. highlight the novel role of TREM2 in shaping the immunosuppressive profile of tumor-associated myeloid cells and report that complementing immune-checkpoint therapy with TREM2 blockade induces stronger anti-tumor immune responses and reduces tumor growth.

Abstract 3555: TREM2 is upregulated and plays oncogenic role in gastric cancer

Abstract Background Triggering receptor expressed on myeloid cells-2 (TREM2) is thought to be invovled in innate immunity and inflammation regulation. More recently, the importance of TREM2 has been highlighted by identification in several kinds of solid tumors. Nonetheless, the oncogenic roles and potential molecular mechanisms of TREM2 in gastric cancer (GC) remain unknown. Methods The expression levels of TREM2 were determined by quantitative PCR (qPCR) and immunohistochemistry (IHC). MTT, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, and in vivo tumorigenicity assays were performed to determine the pro-proliferative role of TREM2 in GC cells. mRNA sequencing, qPCR, and Western blotting were used to explore the underlying molecular mechanism of pro-proliferative role of TREM2 in GC cells. Results The mRNA expression of TREM2 was markedly up-regulated in tumor tissues (n=16) in comparison with that in corresponding non-tumorous tissues. Immunohistochemical study were performed to determine the protein expression in 108 patients with surgically resected GC. Its expression was positively associated with TNM stage (P=0.023) and T classification (P=0.021), and was inversly correlated with the poor clinical outcome of the patients. The human GC cell lines MGC-803 and BGC-823 were used for proliferation analysis. The transfected GC cell lines with stable overexpression of TREM2 were established. Ectopic overexpression of TREM2 in GC cells promoted cell proliferation, whereas loss of TREM2 function inhibited proliferation. In vivo animal experiments further validated the pro-proliferative role of TREM2. Deep sequencing to profile global gene expression of MGC-803 cells with TREM2 overexpression. In the biological process analysis, these differentially expressed genes were mainly involved in the MAPK signaling. Molecular mechanistic investigations explored that TREM2 upregulated GREM1 expression, thereby activating ERK1/2 signaling via VEGFR2-PLC-γ-PKC axis and promoting GC cell proliferation. Conclusion High TREM2 expression predicts poor prognosis in GC and TREM2 promotes GC cells proliferation. Our findings suggest that GREM1-VEGFR2-PLC-γ-PKC-ERK1/2 signaling axis contributes to the oncogenic roles of TREM2 on GC cells. TREM2 could be an effective prognostic biomarker and a potential therapeutic target. Citation Format: Yulong Zheng, Lihua Jiang, Cheng Xiao, Nong Xu, Qiqi Gao, Yinan Yao, Yongxian Hu, Yun Sun, Xin Xu. TREM2 is upregulated and plays oncogenic role in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3555.