Triggering Receptor Expressed On Myeloid Cells 2 Deficiency Research Articles

TREM2 deficiency impairs the energy metabolism of Schwann cells and exacerbates peripheral neurological deficits

Triggering receptor expressed on myeloid cells-2 (TREM2) has been implicated in susceptibility to neurodegenerative disease. Schwann cells (SCs), the predominant glial cell type in the peripheral nervous system (PNS), play a crucial role in myelination, providing trophic support for neurons and nerve regeneration. However, the function of TREM2 in SCs has not been fully elucidated. Here, we found that TREM2 is expressed in SCs but not in neurons in the PNS. TREM2 deficiency leads to disruption of glycolytic flux and oxidative metabolism in SCs, impairing cell proliferation. The energy crisis caused by TREM2 deficiency triggers mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Combined metabolomic analysis demonstrated that energic substrates and energy metabolic pathways were significantly impaired in TREM2-deficient SCs. Moreover, TREM2 deficiency impairs energy metabolism and axonal growth in sciatic nerve, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy. These results indicate that TREM2 is a critical regulator of energy metabolism in SCs and exerts neuroprotective effects on peripheral neuropathy.TREM2 deficiency impairs glycolysis and oxidative metabolism in Schwann cells, resulting in compromised cell proliferation. The energy crisis caused by TREM2 deficiency induces mitochondrial damage and autophagy by activating AMPK and impairing PI3K-AKT-mTOR signaling. Moreover, TREM2 deficiency disrupts the energy metabolism of the sciatic nerve and impairs support for axonal regeneration, accompanied by exacerbation of neurological deficits and suppression of nerve regeneration in a mouse model of acute motor axonal neuropathy (by FigDraw).

TREM2 protects from atherosclerosis by limiting necrotic core formation

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications—myocardial infarction and stroke—are the leading cause of mortality worldwide1,2. Recent studies have identified triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions3, to be highly expressed in macrophage foam cells in experimental and human atherosclerosis4. However, the role of TREM2 in atherosclerosis is not fully known. Here we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased, necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis.

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.

TREM2 regulates microglial phagocytosis of synapses in innate immune tolerance

Increasing evidence indicates that innate immune cells also possess immunological memory. Microglia are brain-resident innate immune cells and execute inflammatory and phagocytic functions upon environmental stimulation, during which processes triggering receptor expressed on myeloid cells 2 (TREM2) plays an important regulatory role. However, although microglia are known to exhibit innate immune memory related to inflammation when subjected to continuous inflammatory stimuli, whether microglia exhibit innate immune memory related to phagocytosis and whether TREM2 participates in innate immune memory of microglia remain unknown. Herein, we treated WT and Trem2 KO mice with peripheral injection of lipopolysaccharides (LPS) to induce microglial activation or microglial immune tolerance. We found that Tnfα and Il-1β expression levels in the hippocampi were significantly elevated after 1xLPS and then dramatically decreased after 4xLPS in both WT and Trem2 KO mice; and their level changes were indistinguishable between WT and Trem2 KO mice. Moreover, 1xLPS significantly promoted microglial phagocytosis of synapses and caused microglial morphology changes resembling activated status in both WT and Trem2 KO mice. However, 4xLPS significantly reduced synapse phagocytosis and largely reversed morphology changes in WT microglia. While 4xLPS had no effect on reducing synapse phagocytosis in Trem2 KO microglia. RNA-seq analysis revealed that TREM2 deficiency reprogrammed complement and phagosome-related transcriptional landscape during immune tolerance. Our results demonstrate that microglia also exhibit immune tolerance related to phagocytosis of synapses and that TREM2 plays a crucial role in this process possibly through regulating complement system and phagosome-related gene expressions.

TREM2 mediates MHCII-associated CD4+ T-cell response against gliomas.

Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors. We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both GBM patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as invivo 2-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres. Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in preclinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres. Our study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found that TREM2 enhances the phagocytosis of tumor cells and promotes an immune response by facilitating MHCII-associated CD4+ T-cell responses against gliomas.

TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson’s Disease Mice and LPS-Induced BV2 Cells

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1β and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1β, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.

The Pathogenesis in Alzheimer's Disease: TREM2 as a Potential Target.

Alzheimer's disease (AD) is ranked as the third-most expensive illness and sixth leading cause of mortality. It is associated with the deposition of extracellular amyloid-β (Aβ) in neural plaques (NPs), as well as intracellular hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs). As a new target in regulating neuroinflammation in AD, triggering receptor expressed on myeloid cells 2 (TREM2) is highly and exclusively expressed on the microglial surface. TREM2 interacts with adaptor protein DAP12 to initiate signal pathways that mainly dominant microglia phenotype and phagocytosis mobility. Furthermore, TREM2 gene mutations confer increased AD risk, and TREM2 deficiency exhibits more dendritic spine loss around neural plaques. Mechanisms for regulating TREM2 to alleviate AD has evolved as an area of AD research in recent years. Current medications targeting Aβ or tau proteins are unable to reverse AD progression. Emerging evidence implicating neuroinflammation may provide novel insights, as early microglia-related inflammation can be induced decades prior to the commencement of AD-related cognitive damage. Physical exercise can exert a neuroprotective effect over the course of AD progression. This review aims to (1) summarize the pathogenesis of AD and recent updates in the field, (2) assess the concept that AD cognitive impairment is closely correlated with microglia-related inflammation, and (3) review TREM2 functions and its role between exercise and AD, which is likely to be an ideal candidate target.

TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination.Graphical

TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment

Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2−/−) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2−/− mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2−/− retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2−/− mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

TREM2 differentially modulates parenchymal and vascular pathology in a mouse model of cerebral amyloid angiopathy

AbstractBackgroundCerebral amyloid angiopathy (CAA) features cerebral vascular deposition of pathological amyloid‐beta protein (Aβ) and plays an important role in the multimorbidity of aging brains including Alzheimer’s disease (AD), but it is less understood compared to parenchymal Aβ plaques. Triggering receptor expressed on myeloid cells 2 (TREM2), a key player in innate immune response, is exclusively expressed in microglia in the brain and mediates Aβ clearance and subsequently alleviates neuroinflammation. Loss‐of‐function mutations in TREM2 increase the risk of AD. Recent studies on TREM2 function using TREM2 knockout (KO) in transgenic (Tg) AD mice have shown that TREM2 modulates parenchymal Aβ deposition in the brain, although the direction of the effect depends on the specific Tg background and the stage of the disease development. However, the impact of TREM2 on CAA had not been investigated.MethodsTREM2 KO mice were crossed with SwDI mice (C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax), a model of CAA and AD, to generate SwDI/TREM2WT, SwDI/TREM2Het, and SwDI/TREM2KO mice. At the age of 16 months, the mice were euthanized for tissue collection. ELISA was utilized for the assessment of Aβ40 and Aβ42 levels in brain tissue homogenates, and histochemical and immunohistochemical or immunofluorescent assays were used to evaluate amyloid deposition, astrogliosis, and microgliosis. All results were analyzed using GraphPad Prism 9.ResultsTREM2 deficiency markedly increased overall Aβ load in SwDI/TREM2KO mice compared to SwDI/TREM2WT or SwDI/TREM2Het in the cortex, hippocampus, and thalamus. Intriguingly, TREM2 deletion led to a dramatic decrease in CAA in vasculature‐enriched regions, such as thalamus, along with reduced microglial association with CAA. Consistent with previous reports, Aβ plaque‐associated microglia were significantly reduced in SwDI/TREM2KO mice. Additional experiments are underway to explore the molecular mechanisms underlying the distinct impact of TREM2 deficiency on Aβ plaques and CAA.ConclusionDeletion of TREM2 increases the overall brain Aβ load whereas decreases CAA, suggesting the differential role of TREM2 in the regulation of parenchymal versus vascular deposition of Aβ in the brain.

Triggering receptor expressed on myeloid cells 2 deficiency exacerbates injury-induced inflammation in a mouse model of tauopathy.

Traumatic brain injury (TBI) promotes several Alzheimer's disease-like pathological features, including microtubule-associated protein tau (MAPT) accumulation within neurons. Macrophage activation in the injured hTau mouse model of tauopathy raises the question whether there is a relationship between MAPT pathology and alterations in macrophage activation following TBI. Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglia and macrophage phenotype, but its mechanisms on TBI remain unclear. To address the association with TREM2 in TBI and MAPT pathology, we studied TREM2 deficiency in hTau mice (hTau;Trem2-/- ) 3 (acute phase) and 120 (chronic phase) days after experimental TBI. At three days following injury, hTau;Trem2-/- mice exhibited reduced macrophage activation both in the cortex and hippocampus. However, to our surprise, hTau;Trem2-/- mice exposed to TBI augments macrophage accumulation in the corpus callosum and white matter near the site of tissue damage in a chronic phase, which results in exacerbated axonal injury, tau aggregation, and impaired neurogenesis. We further demonstrate that TREM2 deficiency in hTau injured mice promotes neuronal dystrophy in the white matter due to impaired phagocytosis of apoptotic cells. Remarkably, hTau;Trem2-/- exposed to TBI failed to restore blood-brain barrier integrity. These findings imply that TREM2 deficiency accelerates inflammation and neurodegeneration, accompanied by attenuated microglial phagocytosis and continuous blood-brain barrier (BBB) leakage, thus exacerbating tauopathy in hTau TBI mice.

TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice.

Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.

TREM2 Ameliorates Lipopolysaccharide-Induced Oxidative Stress Response and Neuroinflammation by Promoting Sirtuin3 in BV2 Cells.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in modulating microglial-mediated neuroinflammation. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) regulates mitochondrial oxidative stress response and neuroinflammation. TREM2 deficiency impairs the denovo synthesis pathway of NAD+. Therefore, the aim of this study was to investigate the potential role of TREM2 and SIRT3 in LPS-induced oxidative stress and neuroinflammation in BV2 cells. Lentivirus vector-mediated TREM2 overexpression (TREM2-OE) and corresponding negative control vector (TREM2-NC) were synthesized. BV2 cells were treated with LPS and/or TREM2-OE. 3-TYP, a selective SIRT3 inhibitor, was applied to determine the role of SIRT3 in the anti-oxidant and anti-inflammatory effects of TREM2. TREM2, SIRT3, NLRP3 inflammasome, caspase-1, postsynaptic density-95 (PSD-95), and brain derived neurotrophic factor (BDNF) were measured by Western blot analysis. Superoxide dismutase (SOD) was tested by SOD Assay Kit. Reactive oxygen species (ROS) expression was examined by immunofluorescence. Interleukin 1β (IL-1β) was determined by ELISA. Contents of NAD+ and NADH were detected by WST-8 method. LPS (1ug/ml for 24h) significantly decreased TREM2 expression at both RNA and protein levels (p < 0.01 and p < 0.05, respectively). Lower levels of SIRT3 protein and NAD+ were also detected following LPS stimulation (p < 0.05 and p < 0.05, respectively). LPS significantly enhanced ROS, NLRP3, caspase-1, and IL-1β expression (p < 0.01, p < 0.05, p < 0.05, and p < 0.01, respectively). PSD-95 and BDNF expression were decreased triggered by LPS (p < 0.05 and p < 0.05, respectively). TREM2 overexpression enhanced NAD+ and SIRT3 protein expression following LPS challenge in BV2 cells (p < 0.01 and p < 0.05, respectively). TREM2 alleviated LPS-induced oxidative stress and neuroinflammation (p < 0.01 and p < 0.05, respectively). Similarly, TREM2 overexpression upregulated PSD-95 and BDNF expression (p < 0.05 and p < 0.05, respectively). The anti-oxidant and anti-inflammatory effects of TREM2 were partially abrogated by SIRT3 antagonist 3-TYP (p < 0.05 and p < 0.05, respectively). Similarly, selective SIRT3 inhibition also partially abrogated TREM2-induced BDNF protein upregulation (p < 0.05) but failed to influence PSD-95 protein expression following LPS stimulation. LPS induces oxidative stress and neuroinflammation in BV2 cells, which may be mediated in part by the downregulation of TREM2 and SIRT3. TREM2 overexpression ameliorates LPS-induced oxidative stress and neuroinflammation through enhancing SIRT3 function via NAD+.

Impact of TREM2 on hippocampal network oscillations in Tg2576 mice modeling amyloid-β pathology.

Loss of function mutations in gene encoding triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with the risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data for indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology in AD. However, mechanisms by which TREM2 contributes to increased predisposition to AD and influences its progression still remain ill-defined. We investigated the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal neuronal network oscillations in wild-type and Aβ overproducing Tg2576 mice by in vivo monitoring spontaneous and brainstem stimulation-induced local field potentials from CA1 region under urethane anesthesia. Functional impairment of TREM2, either in TREM2(Het) or TREM2(Hom), resulted in increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Furthermore, deficiency of TREM2 significantly reduced the power of stimulation-induced hippocampal theta oscillation in Tg2576 mice compared to wild-type mice. However, dysfunction of TREM2 did not influence hippocampal theta-phase gamma-amplitude coupling per se, given that both TREM2 intact and TREM2 total deficient Tg2576 mice had a comparable decrease in the phase-amplitude coupling between theta and gamma oscillations when compared to wild-type counterparts. Our findings indicate a TREM2-dependent microglial function in the hippocampal neuronal network oscillations in both physiological conditions and the setting of Aβ overproduction.

Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages.

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell–expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.

TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.

Triggering receptor expressed on myeloid Cells-2 (TREM2) inhibits steroidogenesis in adrenocortical cell by macrophage-derived exosomes in lipopolysaccharide-induced septic shock

PurposeEndogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock. MethodsThe acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2−/−) mice with lipopolysaccharide (LPS, 30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and for synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2−/− mice and were co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production was assessed. ResultsGenetic deficiency of TREM2 caused significantly higher corticosterone levels at the early stage of LPS-induced septic shock; whereas TREM2 deficiency neither increased CRH and ACTH nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2−/− macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone. Furthermore, Trem2−/− macrophage-derived exosomes were able to mimic Trem2−/− macrophages in enhancing adrenocortical steroidogenesis. ConclusionsAt the early stage of LPS-induced septic shock, corticosterone biosynthesis can be inhibited by macrophage TREM2 in adrenocortical cells, which might partially associate with macrophage-derived exosomes.

Haematopoetic TREM2 deficiency modulates atherosclerosis and lipid metabolism

Background and Aims: Triggering receptor expressed on myeloid cells 2 (TREM2) is a lipid-sensing receptor involved in the regulation of several key myeloid cell functions, including proliferation, survival and phagocytosis. TREM2 is highly expressed on a subset of atherosclerosis-associated aortic macrophages, which express genes associated with lipid metabolism, oxidative stress and calcification while downregulating pro-inflammatory genes. These macrophages correspond to foamy macrophages, which are important players in atherogenesis. Therefore, we sought to investigate the effect of TREM2 deficiency on atherosclerosis.

Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice.

Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in TREM2 signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer's disease (AD). Numerous studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged TREM2-deficient (Trem2-/-) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young Trem2-/- mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged Trem2-/- mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged Trem2-/- mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of TREM2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.SIGNIFICANCE STATEMENT Microglia are innate immune cells of the brain that orchestrates neurodevelopment, synaptic function, and immune response to environmental stimuli. Microglial triggering receptor expressed on myeloid cells 2 (TREM2) signaling plays pivotal roles in regulating these functions and loss of TREM2 signaling leads to increased risk of developing age-related neurologic disorders. However, the neurologic role of TREM2 in normal aging is poorly understood. The results of the present study unveil the positive impacts of TREM2 deficiency on cognitive and synaptic function during aging and suggest that TREM2 may exert detrimental effects on neuronal function. The possibility of age-related negative impacts from TREM2 is critically important since TREM2 has emerged as a major therapeutic target for Alzheimer's dementia.

Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models.

Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.