Triggering Receptor Expressed On Myeloid Cells 2 Research Articles

Effect of triggering receptor expressed on myeloid cells 2-associated alterations on lipid metabolism in macrophages in the development of non-alcoholic fatty liver disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in metabolic homeostasis and inflammatory response. Altered metabolic function in macrophages could modulate their activation and immune phenotype. The present study aimed to investigate the expression of TREM2 in non-alcoholic fatty liver disease (NAFLD) and to clarify the underlying mechanism of TREM2 on macrophages lipid metabolism and oxidative stress. Hepatic TREM2 expression and its relationship with NAFLD progression were analyzed in patients with NAFLD and mice fed a high-fat diet. Lipid metabolism and oxidative stress were investigated in macrophages from NAFLD mice or stimulated with saturated fatty acids. Knockdown and overexpression of TREM2 were further explored. Triggering receptor expressed on myeloid cells 2+ macrophages were increased along with NAFLD development, characterized by aggravated steatosis and liver damage in humans and mice. TREM2 expression was upregulated and lipid metabolism was changed in macrophages from NAFLD mice or metabolically activated by saturated fatty acid in vitro, as demonstrated by increased lipid uptake and catabolism, but reduced de novo synthesis of fatty acids (FAs). Regulation of TREM2 expression in lipid-laden macrophages reprogrammed lipid metabolism, especially the fatty acid oxidation capacity of mitochondria. TREM2 knockdown promoted oxidative stress by aggravating FAs deposition in mitochondria. Intervention of mitochondrial FAs transport in lipid-laden macrophages alleviated FA deposition and reactive oxygen species production induced by TREM2 knockdown. Triggering receptor expressed on myeloid cells 2 expression was associated with the lipid metabolic profile and reactive oxygen species production in macrophages. High expression of TREM2 in macrophages may protect the liver from oxidative stress in NAFLD.

Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Exacerbates Methamphetamine-Induced Activation of Microglia and Neuroinflammation.

Methamphetamine (METH) is a highly addictive psychostimulant and one of the most widely abused drugs worldwide. The continuous use of METH eventually leads to neurotoxicity and drug addiction. Studies have shown that neurotoxicity is strongly associated with METH-induced neuroinflammation, and microglia are the key drivers of neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is reported to play a key role in activation of microglia and neuroinflammation. Yet, the molecular mechanisms by which METH causes neuroinflammation and neurotoxicity remain elusive. In the current study, we investigated the role of TREM2 in neuroinflammation induced by METH in BV2 cells and the wild-type (WT) C57BL/6J mice, CX3CR1GFP/+ transgenic mice, and TREM2 knockout (KO) mice. Postmortem samples from the frontal cortex of humans with a history of METH use were also analyzed to determine the levels of TREM2, TLR4, IBA1, and IL-1β. The expression levels of TREM2, TLR4, IBA1, IL-1β, iNOS, and Arg-1 were then assessed in the BV2 cells and frontal cortex of mice and human METH users. Results revealed that the expression levels of TREM2, TLR4, IBA1, and IL-1β were significantly elevated in METH-using individuals and BV2 cells. Microglia were clearly activated in the frontal cortex of WT C57BL/6 mice and CX3CR1GFP/+ transgenic mice, and the protein levels of IBA1, TREM2, TLR4, and IL-1β were elevated in the METH-induced mouse models. Moreover, TREM2-KO mice showed further increased microglial activation, neuroinflammation, and excitotoxicity induced by METH. Thus, these findings suggest that TREM2 may be a target for regulating METH-induced neuroinflammation.

Nicotinic acid modulates microglial TREM-2 gene in Phytohaemagglutinin-Induced in vitro model of Alzheimer’s disease like pathology

Alzheimer’s disease (AD) is a multifactorial,neurodegenerative disorder linked withextracellular amyloid beta (Aβ) plaques deposition and formation of intracellular neurofibrillary tangles (NFTs). Currently, no effective therapies are available to cure AD. Neuroinflammation isa well-known hallmark in the onset and advancement of AD and triggering receptor expressed on myeloid cells-2 (TREM-2), a microglial gene, is responsible for regulating inflammatory responses and clearance of cellular debris. Loss of TREM-2functionincreases neuroinflammation associated expression of pro-inflammatory markersthus resultingin reduced clearance of Aβ that further aid in disease progression.Therefore, targeting neuroinflammation is a good therapeutic approach for AD. This study aimed to determine the neuroprotective effect of nicotinic acid (NA) in vitro model of AD-like pathology induced in F-98 cell line using Phytohemagglutinin (PHA). MTT assay was employed for checking the cell viability as well as the proliferation of the cells following treatment with NA. PHA at the concentration of 10 μg/mL produces maximum plaques. The neuroprotective effect of NA was next evaluated against PHA-induced plaques and it was observed that NA reverses the damages induced by PHA i.e., by inhibiting the clustering of the cells and replacing the damaged cells with the new ones. Further, NA also increased the expression of TREM-2/DAP-12 with parallel decreased in the expression of IL-1β, TNF-α and iNOS. It also successfully altered disease associated ADAM-10 and BACE-1 compared to PHA control. These findings suggest that NA might be considered as a good therapeutic candidate for the treatment of neurodegenerative disorders like AD.

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.

Inducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associated steatohepatitis (MASH). In animal models of MASH, ICOS was selectively up-regulated on CD8+ T-cells in parallel with an expansion of ICOSL-expressing macrophages. An increase in circulating soluble ICOSL was also evident in patients with MASH as compared to healthy individuals. ICOSL knockout (ICOSL-/-) mice receiving choline/methionine deficient (MCD) diet for 6 weeks had milder steatohepatitis than wild type mice. MASH improvement was confirmed in mice fed with cholesterol-enriched Western diet for 24 weeks in which ICOSL deficiency greatly reduced liver fibrosis along with the formation of crown-like macrophage aggregates producing the pro-fibrogenic mediators osteopontin (OPN) and galectin-3 (Gal-3). These effects associated with a selective shewing of F4-80+/CD11bhigh monocyte-derived macrophages (MoMFs) expressing the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to CD11blow/F4-80+ cells positive for the Kupffer cell marker C-type lectin-like type 2 receptor (CLEC-2), thus indicating an increased MoMF maturation toward monocyte-derived Kupffer cells. These results suggest that CD8+ T-cells interaction with monocyte-derived macrophages through ICOS/ICOSL critically supports a specific subset of TREM2+-expressing cells contributing to the evolution of steatohepatitis. The data also point ICOS/ICOSL dyad as a possible target for therapeutic interventions in MASH.

IPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss.

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

TREM1 is involved in the mechanism between asthma and lung cancer by regulating the Toll‑like receptor signaling pathway.

Lung cancer and asthma are both global health problems with significant economic consequences. Recent studies have demonstrated that asthma may be a risk factor for lung cancer. The present study aimed to explore the pathogenesis between these two diseases through a comprehensive analysis. Differentially expressed genes (DEGs) screened in the asthma-related GSE165934 dataset were analyzed to find relevant inflammatory pathways. Overlapping genes regulated by inflammatory pathways and lung cancer-DEGs from The Cancer Genome Atlas (TCGA) were obtained and subjected to survival and gene-wide mutation analyses, and nomogram construction to determine the hub gene. The hub gene was further analyzed through expression validation, immunoassays and functional experiments to investigate its role and mechanism in lung cancer. Functional enrichment analysis showed that 1,275 DEGs from GSE165934 were closely associated with the Toll-like receptor signaling pathway, and 8 overlapping genes were identified from 12 genes regulated by the Toll-like receptor signaling pathway and 3,134 TCGA-DEGs. After a series of bioinformatics analyses, it was found that triggering receptor expressed on myeloid cells 1 (TREM1) was the hub gene involved in the mechanism of asthma and lung cancer. TREM1 was also found to be a suppressor gene in lung cancer correlated with immune cells, immune checkpoint-related genes and tumor mutational burden score. Additionally, the results of Cell Counting Kit-8 and Transwell experiments demonstrated that overexpression of TREM1 could significantly inhibit the invasion, proliferation and migration of lung cancer cells. Reverse transcription-quantitative PCR and western blotting demonstrated that the overexpression of TREM1 could also significantly reduce the level of Toll-like receptor signaling pathway proteins. The present findings suggest that TREM1 is associated with the mechanism of asthma and lung cancer through its regulation of the Toll-like receptor signaling pathway. Furthermore, TREM1 may serve as a potential treatment target and prognostic indicator for patients with lung cancer.

The role of TREM2 in Alzheimer's disease: from the perspective of Tau.

Triggering receptor expressed on myeloid cells 2 (TREM2), a pattern recognition receptor abundantly expressed on microglia, has been identified as one of the risk factors for Alzheimer's disease (AD). Several studies have already demonstrated the relationship between TREM2 and Tau. TREM2 mutations and altered expression play an important role in Tau phosphorylation. Furthermore, the level of Tau phosphorylation is correlated with soluble TREM2 (sTREM2). However, in different stages of AD, TREM2 seems to have varying effects on Tau pathology. The explicit interaction between TREM2 and Tau, as well as how they affect AD pathology, remains unclear, and there is much evidence to the contrary that requires rational interpretation. Reviewing the dual roles of TREM2 in AD will help identify a more appropriate development strategy for targeting TREM2 to treat AD. Therefore, this review focuses on the interplay between Tau and TREM2 in relation to AD.

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.

Role of trigger receptor 2 expressed on myeloid cells in neuroinflammation－neglected multidimensional regulation of microglia

Neuroinflammation is an inflammatory cascade involved in various neurological disorders, including Alzheimer's disease, multiple sclerosis, and other relevant diseases. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane immune receptor that is primarily expressed by microglia in the central nervous system (CNS). While TREM2 is initially believed to be an anti-inflammatory factor in the CNS, increasing evidence suggests that TREM2 plays a more complex role in balancing neuroinflammation. However, the exact mechanism remains unclear. Notably, TREM2 directly regulates microglia inflammation through various signaling pathways. Additionally, studies have suggested that TREM2 mediates microglial phagocytosis, autophagy, metabolism, and microglia phenotypes, which may be involved in the modulation of neuroinflammation. In this review, we aim to discuss the critical role of TREM2 in several microglia functions and the underlying molecular mechanism the modulatory which further mediate neuroinflammation, and elaborate. Finally, we discuss the potential of TREM2 as a therapeutic target in neuroinflammatory disorders.

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.

Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance.

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.

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.

STREM2 is associated with attenuated tau aggregate accumulation in the presence of amyloid-β pathology.

Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) plays a crucial role in the transition of microglia from a state of homeostasis to a state associated with the disease. Mutations in TREM2 are strongly linked with a higher risk of developing neurodegenerative diseases, including Alzheimer's disease. There have been contradictory findings regarding the potential detrimental or protective effects of microglial activation and TREM2-related microglial responses in Alzheimer's disease. Although previous studies reported increased CSF soluble TREM2 (sTREM2) in different clinical stages of Alzheimer's disease, the exact association between Alzheimer's disease hallmarks such as amyloid-beta and tau pathology remains unclear. In the present study, I aimed to investigate the association between TREM2-related microglial responses and tau accumulation in the presence and absence of amyloid-beta pathology in order to give a better view of the role of microglial activation in Alzheimer's disease development. Imaging data of 178 non-demented participants including 107 amyloid-beta-negative participants, 71 amyloid-beta-positive were recruited from Alzheimer's disease Neuroimaging Initiative. The CSF sTREM2 was used as an in vivo indicator of microglial responses associated with TREM2. Furthermore, I used longitudinal tau-PET and resting-state functional MRI connectomes in order to investigate the association of TREM2-related microglial activation and tau spreading through functional connections. A higher level of sTREM2 was associated with slower tau aggregate accumulation in non-demented amyloid-beta-positive. Furthermore, measuring the tau spreading through inter-connected regions using functional MRI connectomes confirms that the TREM2-related microglial activity might be a protective factor against tau pathology in brain tissue. These findings demonstrate that in individuals with initial amyloid-beta abnormalities, TREM2-related microglial activation is linked to reduced regional accumulation of tau aggregates and also, spreading across inter-connected brain regions, as evaluated through functional MRI connectomes during the early stages of Alzheimer's disease.

Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer’s disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3β pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer’s patients

BackgroundAge-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as “inflammaging” and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown.ObjectivesTo functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant’s own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed.ResultsWe showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers.ConclusionsWe demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.

TREM-1 mediates interaction between substantia nigra microglia and peripheral neutrophils.

Abstract JOURNAL/nrgr/04.03/01300535-202406000-00043/inline-graphic1/v/2023-10-24T010719Z/r/image-tiff Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson’s disease. Triggering receptor expressed on myeloid cell-1 (TREM-1) can amplify the inherent immune response, and crucially, regulate inflammation. In this study, we found marked elevation of serum soluble TREM-1 in patients with Parkinson’s disease that positively correlated with Parkinson’s disease severity and dyskinesia. In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease, we found that microglial TREM-1 expression also increased in the substantia nigra. Further, TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson’s disease and reduced dopaminergic neuronal injury. Meanwhile, TREM-1 knockout attenuated the neuroinflammatory response, dopaminergic neuronal injury, and neutrophil migration. Next, we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson’s disease and treated the cells with the TREM-1 inhibitory peptide LP17. We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration. Moreover, inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide. TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK. These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson’s disease by regulating the interaction between microglia and peripheral neutrophils.

Is triggering receptor expressed on myeloid cell 1 (TREM-1) protein a new marker of serious infectious complications in colorectal surgery?: case-matched pilot study

PurposeThe purpose of the study was to evaluate the usefulness of the triggering receptor expressed on myeloid cell 1 (TREM-1) protein as a marker for serious infectious complications during laparoscopic colorectal surgery.MethodsSixty-four patients with colon or rectal cancer, who underwent an elective laparoscopic colorectal cancer surgery from November 2018 to February 2020, were included in the analysis. Blood samples of the TREM-1 protein testing were collected four times from each patient: before and on three following postoperative days (PODs). Patients were divided into two groups according to the presence of infectious complications. Subsequently, patients with infectious complications (group 1) were matched 1:1 with patients without complications (group 2). The case-matched analysis was done by selecting patients from the control group by age, ASA scale, cancer stage, and type of surgery.ResultsThere was no significant difference in demographic and operative characteristics between the two groups. The median length of hospital stay was longer in group 1 than in group 2 (11 days vs. 5 days, p < 0.001). Preoperative measurements of TREM-1 protein did not differ between the two groups. There were no significant differences in the measurements on the first and third postoperative days. However, the median TREM-1 measurement was higher in group 1 on the second postoperative day (542 pg/ml vs. 399 pg/ml; p = 0.040). The difference was more apparent when only severe postoperative complications were considered. When compared to the group without any complications, the median TREM-1 level was significantly higher in the group with severe infection complications in POD 1, POD 2, and POD 3 (p < 0.05). The receiver operating characteristic (ROC) curve demonstrated that TREM-1 readings in POD 2 had a sensitivity of 83% and a specificity of 84% for the presence of severe infection complications at a value of 579.3 pg/ml (AUC 0.8, 95%CI 0.65–0.96).ConclusionTREM-1 measurements might become a helpful predictive marker in the early diagnosis of serious infectious complications in patients following laparoscopic colorectal surgery.

Pyrolae herba alleviates cognitive impairment via hippocampal TREM2 signaling modulating neuroinflammation and neurogenesis in lipopolysaccharide-treated mice

Ethnopharmacological relevancPyrolae herba (PH), a kind of Chinese herb, has been identified to have an anti-inflammatory effect, while the potential for treating cognitive impairment (CI), as well as the underlying mechanisms, is unclear. Currently, the interaction between neuroinflammation and neural function play a critical role in pathophysiology of CI. Aim of the studyTo elucidate therapeutic effect of PH for CI as well as its underlying mechanisms with LPS-treated mice model. Methods and materialsIn this study, male C57BL6/J mice received lipopolysaccharide (LPS) injection for 10 days to establish CI model and were administrated with PH for 14 days. We used piracetam as a positive control. Memory and spatial function was tested by Morris water maze (MWM). The level of inflammation-related cytokines (TNF-α, IL-1β, IL-10, IL-6) were determined by enzyme-linked immunosorbent assay (ELISA) in serum and western blot in hippocampus. Immunofluorescence (IF) was used to measure the levels of ionized calcium binding linker molecule 1 (IBA-1), glial fibrillary acidic protein (GFAP), BrdU, Ki67 and doublecortin (DCX) in hippocampus. The mRNA sequencing was used to screen the potential target of PH with therapeutic CI. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene alteration of triggering receptor expressed on myeloid cells 2 (TREM2) in hippocampus. We used western blot to determine protein expressions of TREM2 and its related signaling, as well as synaptic proteins in hippocampus. ResultsThe results revealed that LPS contributed to CI, and PH or piracetam treatment significantly ameliorated CI in MWM test. LPS contributed to increasing expressions of TNF-α and IL-1β in serum and hippocampus, which both reversed by PH or piracetam. PH or piracetam could inhibit the activation of glial cells including microglia and astrocyte in the hippocampus in LPS-induced CI model. The mRNA sequencing and RT-PCR results showed that LPS significantly increased the gene expression of TREM2, which was reversed by PH. The alteration of TREM2 expression was the most significant among the 10 genes (TREM2, Slc24a2, Ptch2, Gck, Il1rapl1, Cadps2, Btbd11, Secisbp2l, Tenm3 and Prepl) in hippocampus. Protein results showed that LPS upregulated the expressions of TREM2 and its related proteins including DAP12, spleen tyrosine kinase (SYK) phosphorylation and ADAM 10, which were all reversed by PH or piracetam in hippocampus. Furthermore, LPS was capable of reducing the expression of BrdU and DCX co-labeled positive cells in hippocampal dentate gyrus (DG), which was reversed only by PH. Moreover, PH or piracetam treatment significantly increased the expression of Ki67 and DCX co-labeled positive cells in hippocampal DG. The expression of synapsin1 was obviously decreased by LPS and was significantly reversed by PH or piracetam. ConclusionsPH could alleviate CI by suppressing the secretion of pro-inflammatory cytokines and mitigating astrocyte activity by restraining microglia's activation in hippocampus, further facilitating neurogenesis and proliferation, thereby enhancing pre-synaptic protein. This study highlighted on the clinical application of PH, which might promote the use of phytomedicine in CI patients.

Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10-5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; pprefrailty = 1 × 10-15 , pfrailty = 2 × 10-19 ), transgelin (TAGLN; pprefrailty = 2 × 10-12 , pfrailty = 6 × 10-22 ), and insulin-like growth factor-binding protein 2 (IGFBP2; pprefrailty = 5 × 10-15 , pfrailty = 1 × 10-15 ) and with a lower level of growth hormone receptor (GHR, pprefrailty = 3 × 10-16 , pfrailty = 2 × 10-18 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10-5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

Curcumin-activated Olfactory Ensheathing Cells Improve Functional Recovery After Spinal Cord Injury by Modulating Microglia Polarization Through APOE/TREM2/NF-κB Signaling Pathway

Transplantation of curcumin-activated olfactory ensheathing cells (aOECs) improved functional recovery in spinal cord injury (SCI) rats. Nevertheless, little is known considering the underlying mechanisms. At the present study, we investigated the promotion of regeneration and functional recovery after transplantation of aOECs into rats with SCI and the possible underlying molecular mechanisms. Primary OECs were prepared from the olfactory bulb of rats, followed by treatment with 1µM CCM at 7–10 days of culture, resulting in cell activation. Concomitantly, rat SCI model was developed to evaluate the effects of transplantation of aOECs in vivo. Subsequently, microglia were isolated, stimulated with 100 ng/mL lipopolysaccharide (LPS) for 24 h to polarize to M1 phenotype and treated by aOECs conditional medium (aOECs-CM) and OECs conditional medium (OECs-CM), respectively. Changes in the expression of pro-inflammatory and anti-inflammatory phenotypic markers expression were detected using western blotting and immunofluorescence staining, respectively. Finally, a series of molecular biological experiments including knock-down of triggering receptor expressed on myeloid cells 2 (TREM2) and analysis of the level of apolipoprotein E (APOE) expression were performed to investigate the underlying mechanism of involvement of CCM-activated OECs in modulating microglia polarization, leading to neural regeneration and function recovery. CCM-activated OECs effectively attenuated deleterious inflammation by regulating microglia polarization from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype in SCI rats and facilitated functional recovery after SCI. In addition, microglial polarization to M2 elicited by aOECs-CM in LPS-induced microglia was effectively reversed when TREM2 expression was downregulated. More importantly, the in vitro findings indicated that aOECs-CM potentiating LPS-induced microglial polarization to M2 was partially mediated by the TREM2/nuclear factor kappa beta (NF-κB) signaling pathway. Besides, the expression of APOE significantly increased in CCM-treated OECs. CCM-activated OECs could alleviate inflammation after SCI by switching microglial polarization from M1 to M2, which was likely mediated by the APOE/TREM2/NF-κB pathway, and thus ameliorated neurological function. Therefore, the present finding is of paramount significance to enrich the understanding of underlying molecular mechanism of aOECs-based therapy and provide a novel therapeutic approach for treatment of SCI.