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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. 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. 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.

IgA nephropathy (IgAN) is a common type of primary glomerulonephritis in children. The pathogenesis of childhood IgAN remains unclear, and there is a lack of effective non‐invasive biomarkers for this disease. Single‐cell RNA sequencing was performed in children with IgAN to delineate cellular and molecular compositions, and subcluster analysis for macrophages was conducted. Blood samples were collected from 38 children with IgAN to measure soluble TREM2 (sTREM2) and soluble CD163 (sCD163) levels and analyse their clinical significance. Single‐cell RNA sequencing identified distinct cell clusters in both parenchymal and stromal compartments. Mesangial components were classified into vascular smooth muscle cells/pericytes, mesangial cells, fibroblasts and activated myofibroblasts. Patients with IgAN had a marked increase in myofibroblasts and immune cells in comparison to the control group. Remarkable infiltration of macrophages was observed in the kidneys of IgAN patients, and a subgroup of marcophages with high TREM2 expression was enriched. Children with IgAN exhibited significantly higher plasma sTREM2 levels than healthy individuals, and the sTREM2 level was correlated with sCD163 abundance. Importantly, an increased sTREM2 level was positively associated with the severity of proteinuria. Moreover, the elevation of sTREM2 was correlated with a more advanced pathological grading. In summary, we unveiled a remarkable remodelling of the stromal cellular landscape in childhood IgAN, and TREM2 + macrophages were found to accumulate. We identified that the plasma sTREM2 level was associated with clinical and pathological severity and therefore constituted a potential non‐invasive biomarker for children with IgAN. What is the central question of this study? The evolution of cellular composition during progression of childhood IgA nephropathy (IgAN) is complex and remains unclear. There is a lack of an efficient non‐invasive biomarker for childhood IgAN. What is the main finding and its importance? Using single‐cell RNA sequencing, we revealed the cellular landscape of childhood IgAN by including distinct subpopulations among mesangial‐like cells and macrophages. A subgroup of TREM2 + macrophages accumulated in the kidney of childhood IgAN patients. The soluble TREM2 level was correlated with the clinical and pathological severity of disease, serving as a reliable non‐invasive biomarker for IgAN.

The pathological basis underlying mild traumatic brain injury (mTBI)-induced long-term cognitive impairment is not fully understood. It is supposed that mTBI induces residential microglia activation rather than peripheral leukocyte infiltration to promote neuroinflammation, thus triggering myelin damage as well as cognitive impairment. The transformation of microglia towards a pro-inflammatory (M1 type) or anti-inflammatory (M2 type) state is critical for restraining the cerebral inflammatory response to acute or chronic insults. In addition to classical M1- and M2-like phenotypes, a specific subgroup of microglia, which is referred to as disease-associated microglia (DAM), the transition of which is regulated by triggering receptor expressed on myeloid cells 2 (Trem2), is also demonstrated to play a critical role in neurodegenerative diseases sharing similar pathological procedures to mTBI. The expression and function of p75 neurotrophin receptor (p75NTR) in microglia vary depending on the type and severity of the specific pathological stimuli. In the current study, we investigated whether peripheral leukocytes infiltrated the brain following mild traumatic brain injury (mTBI) using a CX3CR1- and CCR2-double transgenic reporter mouse model. We also examined whether M1- or M2-like microglia exhibited a disease-associated microglia (DAM) phenotype after mTBI, as indicated by their Trem2 expression. Then we explored the expression of p75NTR in M1- and M2-like phenotype microglia after mTBI and its modulating effects on the activation of Trem2 positive M1- and M2-like phenotype microglia, neuroinflammatory reaction, myelin damage, and cognitive performance. We found that most of the activated residential microglia after mTBI were Trem2 positive and p75NTR expression was significantly elevated in Trem2-positive M1-type microglia post-mTBI, correlating with increased pro-inflammatory cytokine release, demyelination, and cognitive deficits. Pharmacological blockade of p75NTR using the antagonist TAT-Pep5 suppressed M1 microglial activation, reduced neuroinflammation, and restored myelin integrity, leading to marked improvements in cognitive function. Mechanistically, p75NTR exhibited a cell-type-specific regulatory role in neuroinflammatory responses, potentially through interacting with Trem2 to modulate DAM-like microglia activation. These findings highlight p75NTR as a key mediator of mTBI-induced neuropathology and propose its inhibition as a novel therapeutic strategy to mitigate secondary neuroinflammation and cognitive decline.

Background TREM2 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. Methods The 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. Results Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230 ), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222 ) and ENST00000338469 (TREM2 219 ), 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. Conclusions TREM2 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.

INTRODUCTION Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2–apoE3 interactions and effects of AD‐associated variants on TREM2–apoE3 interactions are not fully understood. METHODS We used consensus protein–protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2–apoE3 complex structure and examine AD‐associated TREM2 R47H, and apoE4 variants effects. RESULTS Our experimentally consistent TREM2–apoE3 complex structure identified new potential TREM2–apoE3 interactions alongside the known interactions. TREM2–apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD‐associated TREM2 R47H and apoE4  variants altered TREM2–apoE binding mode and conformational stability. DISCUSSION This study determined an experimentally consistent TREM2–apoE3 complex structure and revealed a potential mechanism that AD‐associated TREM2 R47H variant alters TREM2–apoE3 binding mode. Understanding TREM2–apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD‐associated variants. Highlights Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally consistent TREM2–apoE3 complex structure was determined. New potential interaction interfaces between TREM2 and apoE3 were identified. TREM2–apoE3 interactions altered TREM2 and apoE3 conformation. AD‐associated TREM2  R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2–apoE complexes.

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.

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer’s disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2 +/+ (T2+/+) and Trem2 −/− (T2−/−) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2−/−PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2−/−PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex comparedwith T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2−/−PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.

Background Low frequency coding variants in TREM2 are associated with Alzheimer disease (AD) risk and cerebrospinal fluid (CSF) TREM2 protein levels are different between AD cases and controls. Similarly, TREM2 risk variant carriers also exhibit differential CSF TREM2 levels. TREM2 has three different alternative transcripts, but most of the functional studies only model the longest transcript. No studies have analyzed TREM2 expression levels or alternative splicing in brains from AD and cognitively normal individuals. We wanted to determine whether there was differential expression of TREM2 in sporadic-AD cases versus AD- TREM2 carriers vs sex- and aged-matched normal controls; and if this differential expression was due to a particular TREM2 transcript. Methods We analyzed RNA-Seq data from parietal lobe brain tissue from AD cases with TREM2 variants ( n  = 33), AD cases ( n  = 195) and healthy controls ( n  = 118), from three independent datasets using Kallisto and the R package tximport to determine the read count for each transcript and quantified transcript abundance as transcripts per million. Results The three TREM2 transcripts were expressed in brain cortex in the three datasets. We demonstrate for the first time that the transcript that lacks the transmembrane domain and encodes a soluble form of TREM2 (sTREM2) has an expression level around 60% of the canonical transcript, suggesting that around 25% of the sTREM2 protein levels could be explained by this transcript. We did not observe a difference in the overall TREM2 expression level between cases and controls. However, the isoform which lacks the 5′ exon, but includes the transmembrane domain, was significantly lower in TREM2 - p.R62H carriers than in AD cases ( p  = 0.007). Conclusion Using bulk RNA-Seq data from three different cohorts, we were able to quantify the expression level of the three TREM2 transcripts, demonstrating: (1) all three transcripts of them are highly expressed in the human cortex, (2) that up to 25% of the sTREM2 may be due to the expression of a specific isoform and not TREM2 cleavage; and (3) that TREM2 risk variants do not affect expression levels, suggesting that the effect of the TREM2 variants on CSF levels occurs at post-transcriptional level.

Beta-amyloid deposition is a defining feature of Alzheimer’s disease (AD). How genetic risk factors, like APOE and TREM2 , intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with varied APOE and TREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases with APOE and TREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating that APOE and TREM2 risk variants are associated with a significant reduction in CD163-positive amyloid-responsive microglia. Our results showcase the diverse microglial response in AD and underscore how genetic risk factors influence cellular responses to underlying pathologies.

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro . In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state. Synopsis This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease. An antibody directed to the stalk region of TREM2 prevents its shedding and increases cell autonomous signaling. Addition of this TREM2 antibody to myeloid cells in vitro stimulates phagocytosis, and improves cell survival. TREM2 antibody treatment increases TREM2 expression on brain microglia, decreases homeostatic markers and reduces amyloid plaque pathology in a mouse model of Alzheimer's disease. Antibody mediated stimulation of TREM2 signaling may be efficacious in Alzheimer's disease as well as other neurodegenerative disorders and obesity‐associated metabolic syndromes. Graphical Abstract This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease.