HIV gp120 induces TREM1 expression through TLR-PGE₂ signalling in human monocyte-derived microglia.

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Learn more: PMC Disclaimer | PMC Copyright Notice J Neuroinflammation . 2026 Mar 5;23:118. doi: 10.1186/s12974-026-03757-8 Search in PMC Search in PubMed View in NLM Catalog Add to search HIV gp120 induces TREM1 expression through TLR–PGE₂ signalling in human monocyte-derived microglia Ayisha Mahama Ayisha Mahama 1 Division of Basic and Translational Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD USA Find articles by Ayisha Mahama 1 , Pratima Rawat Pratima Rawat 2 Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA USA 4 Microbiologics, Inc, San Diego, CA USA Find articles by Pratima Rawat 2, 4 , Carmen Teodorof-Diedrich Carmen Teodorof-Diedrich 2 Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA USA Find articles by Carmen Teodorof-Diedrich 2 , Stephen A Spector Stephen A Spector 2 Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA USA 3 Rady Children’s Hospital, San Diego, CA USA Find articles by Stephen A Spector 2, 3 , Grant R Campbell Grant R Campbell 1 Division of Basic and Translational Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD USA Find articles by Grant R Campbell 1, ✉ Author information Article notes Copyright and License information 1 Division of Basic and Translational Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD USA 2 Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA USA 3 Rady Children’s Hospital, San Diego, CA USA 4 Microbiologics, Inc, San Diego, CA USA ✉ Corresponding author. Received 2025 Jul 4; Accepted 2026 Feb 25; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13069711  PMID: 41782012 Abstract Microglia serve as a long-lived reservoir for HIV in the brain and are resistant to the cytopathic effects of infection. As such, they pose a significant barrier to eradication strategies and contribute to chronic neuroinflammation in people living with HIV. We previously identified that triggering receptor expressed on myeloid cells-1 (TREM1) is upregulated in HIV-infected human microglia and is associated with resistance to virus-associated cellular stress. In this study, we examined the upstream mechanisms by which the HIV-1 envelope protein gp120 induces TREM1 expression in human monocyte-derived microglia. We found that gp120 induces TREM1 transcription through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) signalling, and that this process requires prostaglandin E₂ (PGE₂) signalling through prostaglandin E₂ receptor EP4. Inhibition of TREM1 increased apoptotic DNA fragmentation and cytotoxicity in gp120-exposed microglia, consistent with a functional contribution of TREM1 in modulating apoptotic signalling under these conditions. Together, these findings identify a TLR–PGE₂–TREM1 signalling axis that regulates innate immune responses and apoptotic marker modulation following HIV-1 envelope protein exposure. Given the contribution of long-lived microglia to HIV-associated neurocognitive disorders, the TREM1 pathway may represent a therapeutic target for modifying neuroinflammatory responses in the context of HIV infection. Keywords: Microglia, TREM1, HIV, gp120, PGE₂, Toll-like receptor, Neuroinflammation Introduction Microglia are the resident macrophages of the central nervous system (CNS) and play key roles in maintaining neuronal homeostasis, shaping synaptic circuits, and orchestrating immune responses to pathogens and injury [ 1 , 2 ]. Their long lifespan (approximately 4 years), capacity for self-renewal, and resistance to HIV-induced cytopathogenesis enable them to serve as a stable, long-lived HIV reservoir [ 3 – 7 ]. Consequently, microglia may contribute to intermittent viral blips during suppressive antiretroviral therapy (ART), which are associated with ART resistance, HIV-associated neurocognitive disorders (HAND) [ 8 – 10 ], and viral rebound following ART interruption or failure [ 11 – 14 ]. Thus, their role as a latent reservoir within the CNS is increasingly recognised [ 15 – 17 ]. Microglia detect pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), initiating pro-inflammatory or microbicidal responses [ 18 , 19 ]. PRRs including toll-like receptors (TLRs), NOD-like receptors (NLRs), retinoic acid–inducible gene I (RIG-I)–like receptors, AIM2-like receptors (ALRs), C-type lectin receptors (CLRs), and triggering receptors expressed on myeloid cells (TREMs) recognise conserved molecular motifs such as nucleic acids, peptidoglycans, and glycan polymers [ 19 , 20 ]. Several of these PRRs detect HIV-encoded PAMPs: TLR10 binds gp41; cGAS and IFI16 recognise HIV DNA [ 21 , 22 ]; RIG-I, IFIH1, TLR7, and TLR8 detect HIV RNA [ 23 – 28 ]; and the envelope glycoprotein gp120, one of the most heavily glycosylated viral proteins, is recognised by CD209, MBL2, MRC1, TLR2, and TLR4 [ 29 – 32 ]. TLR2 and TLR4 are among the best-characterised PRRs in microglia. Upon activation, they recruit adaptor proteins via their TIR domains to initiate downstream signalling pathways, leading to the production of pro-inflammatory cytokines and chemokines [ 20 , 33 , 34 ]. TLR activation has been shown to upregulate TREM1 expression [ 35 , 36 ], which enhances and sustains inflammatory signalling in synergy with TLRs and NLRs [ 36 – 41 ]. Elevated TREM1 expression drives pathological neuroinflammation and contributes to various CNS disorders, including Alzheimer’s disease [ 42 – 44 ], Parkinson’s disease [ 45 ], subarachnoid haemorrhage [ 46 – 49 ], and glioblastoma [ 50 ]. HIV gp120, beyond its essential role in viral entry, is shed as a soluble protein from virions and infected cells [ 51 ], and is internalised by uninfected bystander cells in the CNS of people living with HIV (PLWH) [ 5 ]. Thus, gp120 alone serves as a relevant stimulus to dissect the early innate responses of microglia, independent of productive infection. Soluble gp120 contributes to neuronal damage both directly, through disruption of dopaminergic neurons, cytoskeletal architecture, and mitochondrial function [ 52 , 53 ], and indirectly by activating microglia, leading to the release of pro-inflammatory mediators, chemokines, and excitotoxins [ 54 , 55 ]. This exacerbates neuroinflammation and may underlie the persistence of HAND despite virologically suppressive ART [ 56 , 57 ]. Given the role of TREM1 in amplifying neuroinflammation and the capacity of soluble gp120 to activate microglia, we sought to determine how exposure to gp120 influences TREM1 expression in human microglia. To our knowledge, the upstream mechanisms by which gp120 regulates TREM1 expression in human microglia have not been previously defined. Elucidating these pathways may provide insight into mechanisms contributing to persistent neuroinflammation and cognitive dysfunction in people living with HIV despite effective ART. Accordingly, we investigated the innate immune signalling pathways through which gp120 modulates TREM1 expression in human monocyte-derived microglia. Materials and methods Microglia culture Peripheral blood mononuclear cells (PBMC) were isolated from whole blood using density gradient centrifugation with Ficoll-Paque Plus (Cytiva). Human monocyte-derived microglia (MMG) were differentiated from primary human monocytes according to previously established methods [ 58 – 61 ]. In brief, 6 × 10 6 PBMC mL − 1 were cultured in MMG media (RPMI 1640 Glutamax supplemented with 100 U mL − 1 penicillin, 100 µg mL − 1 streptomycin [all Gibco], 10 ng mL − 1 β-NGF, 100 ng mL − 1 CCL2, 10 ng mL − 1 CSF1, 10 ng mL − 1 CSF2, and 100 ng mL − 1 IL-34 [all R&D Systems]) for 4 h. Non-adherent cells were removed by aspiration, and the adherent cells were washed with Dulbecco’s phosphate-buffered saline (Gibco). These cells were then incubated in microglia media for 14 d at 37 °C in a humidified 5% CO 2 incubator, with media changes every 3 d before use. All experiments were performed using MMG derived from ≥ 4 independent human donors ( n = 4) per condition, with biological replicates as detailed in figure legends. Chemicals Recombinant HIV‑1 gp120 Ba-L (Cat# HRP‑20082) was obtained through the NIH HIV Reagent Program, Division of AIDS (DAIDS), NIAID, NIH. The reagent is distributed by BEI Resources on behalf of the NIH HIV Reagent Program. HIV-1 gp120 was reconstituted in sterile PBS to create a stock solution and diluted to a working concentration of 2 ng mL⁻¹ in culture medium. Equivalent PBS volumes were included as vehicle controls. 2 ng mL⁻¹ was selected based on prior studies demonstrating robust microglial signalling responses at low-nanomolar concentrations without inducing nonspecific cytotoxicity [ 62 , 63 ]. Anti-HIV-1 gp120 monoclonal antibody VRC01 (Cat# 12033) was also obtained through the NIH HIV Reagent Program from John Mascola [ 64 ]. For use in neutralisation assays and specificity controls, VRC01 was utilised at a concentration of 5 µg mL⁻¹ [ 65 ]. The paired isotype control IgG1 was purchased from Abcam (Cat# ab288147, RRID: AB_3073783). Lipopolysaccharide (LPS) (Cat# L2630), EGTA (Cat# E0396), and L-798,106 (Cat# L4545) were purchased from Sigma; trypsin was purchased from Gibco (Cat# 25200). Celecoxib (Cat# S1261), KN93 (Cat# S6787), maraviroc (Cat# S2003), PF 04418948 (Cat# S7211), SC560 (Cat# S6686), and tacrolimus (Cat# S5003) were purchased from Selleck Chemicals, MF63 (Cat# A3600), was purchased from ApexBio; SC51322 (Cat# 1292), was purchased from Tocris; and E7046 (Cat# HY-103088), was purchased from MedChemExpress. Small-molecule inhibitors were used at concentrations based on reported IC₅₀ values for their respective targets and applied as mechanistic probes. Concentrations were selected to minimise nonspecific cytotoxicity, as confirmed by lactate dehydrogenase (LDH) release assays under experimental conditions. All small-molecule inhibitors were reconstituted in anhydrous DMSO (Sigma-Aldrich, Cat# D2650) or water according to manufacturer instructions and diluted in culture medium to a final DMSO concentration not exceeding 0.1%. Vehicle-only (DMSO) controls were included in all experiments. Cell death and inflammatory markers Apoptotic single-stranded DNA (ssDNA) was quantified using a monoclonal anti-ssDNA antibody (Enzo Life Sciences, Cat# ALX-804-192, RRID: AB_10541559), as previously described [ 66 ]. LDH activity in cell culture supernatants was measured using the CyQuant LDH Cytotoxicity Assay (Invitrogen, Cat# C20301 ), with percentage cytotoxicity calculated according to the manufacturer’s protocol. The ssDNA ELISA selectively detects apoptotic DNA fragmentation, while LDH release reflects membrane lysis associated with necrotic or late apoptotic death. Prostaglandin E₂ (PGE₂) levels in supernatants were measured using a forward sequential competitive enzyme immunoassay kit (R&D Systems, Cat# SKGE004B). Tumour necrosis factor (TNF) and interleukin-10 (IL-10) were quantified using the Human TNF-alpha DuoSet ELISA Kit (R&D Systems, Cat# DY210) and the Human IL-10 DuoSet ELISA (R&D Systems, Cat# DY217B), respectively. Extracellular WARS1 concentrations were quantified using the human tryptophanyl-tRNA synthetase, WARS ELISA Kit (Cusabio, Cat# CSB-E11789h). Spike-and-recovery controls were performed in conditioned media to confirm assay performance. Small interfering RNA transfection MMG were transfected with Ambion Silencer Select siRNA targeting NFATC1 (ID# s9470), RELA (ID# s11915), TLR2 (ID# s76898), TLR4 (ID# s14195), or non-targeting control siRNA (Silencer Select Negative Control No. 2; Cat# 4390846) using Lipofectamine RNAiMAX (Thermo Fisher) in Opti-MEM (Gibco), following the manufacturer’s instructions. siRNA was used at a final concentration of 10 nM for all targets. For CCR5 silencing, MMG were transfected with Ambion Silencer siRNA targeting CCR5 (ID# 1987) or a non-targeting control siRNA (Silencer Negative Control No. 1; Cat# AM4611) using Lipofectamine 2000 (Invitrogen), which yielded robust and reproducible CCR5 knockdown in MMG under these conditions. Cells were analysed for target gene knockdown 48 h post-transfection and subsequently used in downstream experiments. Transfection efficiency was assessed using BLOCK-iT Alexa Fluor Red Fluorescent Control (Invitrogen) and quantified on a Countess 3 FL automated cell counter (Thermo Fisher). Western blotting Cell lysis was performed using a buffer containing 20 mM HEPES (Gibco), 150 mM NaCl (Fisher), and 1 mM EDTA (Sigma), supplemented with 1% (vol/vol) Triton X-100 (Sigma) and 1% (vol/vol) Halt protease and phosphatase inhibitor cocktail (Thermo Scientific). Lysates were resolved on polyacrylamide gels buffered with 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol/3-(N-morpholino)propanesulphonic acid buffer, transferred to 0.45 μm nitrocellulose membranes (Thermo Scientific), and incubated overnight at 4 °C with primary antibodies. Detection was carried out using alkaline phosphatase-conjugated secondary antibodies (Invitrogen; Cat# WP20007, RRID: AB_2924319; or Cat# WP20006, RRID: AB_2924320), followed by the application of 0.25 mM CDP-Star supplemented with 5% (vol/vol) Nitro-Block II (both Applied Biosystems). Primary antibodies used for western blotting were anti-ACTB (β-actin; Cat# 4967, RRID: AB_330288); anti-BAD (Cat# 9268 S, RRID: AB_823433); anti-BAX (Cat# 5023, RRID: AB_2744530); anti-BCL2 (Cat# 15071, RRID: AB_2744528); anti-BCLXL (Cat# 2764, RRID: AB_2228008); anti-NFATC1 (Cat# 8032, RRID: AB_10829466); anti-PTGS1 (Cat# 9896, RRID: AB_10860249); anti-PTGS2 (Cat# 12282, RRID: AB_2571729); anti-RELA (Cat# 8242, RRID: AB_10859369); anti-TLR2 (Cat# 12276, RRID: AB_2797867); and anti-TLR4 (Cat# 38519, RRID: AB_2924306), all from Cell Signaling Technology. Additional antibodies used included anti-CCR5 (BD Pharmingen, Cat# 555991, RRID: AB_10118300), anti-PTGES (Novus, Cat# NBP3-15084, RRID: AB_2925176), anti-PTGES3 (Novus, Cat# NB110-96879, RRID: AB_1260817), anti-TREM1 (Abcam, Cat# ab90808, RRID: AB_2050414), anti-TREM1 (R&D Systems, Cat# MAB1278, RRID: AB_2208452), and anti-ACTB (β-actin; Sigma, Cat# A2228, RRID: AB_476697). Anti-TREM1 (R&D Systems) and anti-ACTB (Sigma) were used selectively for the CCR5 knockdown experiments, while anti-TREM1 (Abcam) and anti-ACTB (Cell Signaling Technology) were used throughout all other experiments, reflecting reagent availability at the time the experiments were performed. These antibodies were validated within the same experimental set and were not used for cross-figure quantitative comparisons. Protein band intensities were quantified using Fiji (ImageJ developed by the Max Planck Institute of Molecular Cell Biology and Genetics [ 67 ]; RRID: SCR_002285) and normalised to ACTB as a loading control. Quantitative PCR Total RNA was extracted from cell pellets using the RNeasy Mini Kit (Qiagen), following the manufacturer’s instructions. RNA concentrations were measured using a NanoDrop 1000 spectrophotometer. Complementary DNA (cDNA) was synthesised using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems), in accordance with the manufacturer’s protocol. Quantitative polymerase chain reaction (qPCR) was conducted using an Applied Biosystems QuantStudio 384-well real-time qPCR system with TaqMan Fast Advanced Master Mix and commercially available probes targeting PTGES (Hs00610420_m1; FAM-MGB), PTGES3 (Hs04187819_g1; FAM-MGB), PTGS1 (Hs00377726_m1; FAM-MGB), PTGS2 (Hs00153133_m1; FAM-MGB), and TREM1 (Hs00218624_m1; FAM-MGB), as well as the reference gene POLR2A (Hs00172187_m1; VIC-MGB), all from Applied Biosystems. Relative quantification of target gene expression, normalised to the reference gene, was calculated using the Pfaffl method [ 68 ]. Resulting data were normalised to the vehicle control and log₂ transformed for subsequent analysis. Statistics Samples were allocated to experimental groups using simple random sampling. Sample size (n) was determined based on preliminary effect sizes observed in pilot experiments and power calculations assuming 80% power and α = 0.05. Data symmetry or skewness was evaluated using Pearson’s skewness coefficient. Normalised ratiometric data were log₂-transformed prior to analysis. Comparisons were conducted using a paired, two-tailed Student’s t -test or, where applicable, two-way repeated-measures ANOVA with Bonferroni-corrected post-hoc tests. Statistical significance was defined as p < 0.05. Data are presented as scatter plots showing arithmetic means ± standard deviation (SD). Each data point represents an individual donor. Paired samples from each donor were used across all treatment conditions. Results HIV gp120 induces TREM1-associated modulation of apoptotic markers in microglia Previous studies have shown that HIV infection and the viral protein Tat are associated with increased TREM1 expression in macrophages and microglia, and with altered regulation of apoptotic signalling pathways [ 69 – 71 ]. However, whether the HIV envelope glycoprotein gp120 alone is sufficient to induce TREM1 expression and associated apoptotic marker modulation in human microglia has not been defined. Given this, we designed experiments to investigate whether HIV gp120 modulates apoptotic regulatory pathways in microglia through TREM1 upregulation. We observed that gp120 dose-dependently increased the expression of the anti-apoptotic proteins BCL2 (B-cell lymphoma 2) and BCLXL (B-cell lymphoma extra-large), while reducing pro-apoptotic BAD (BCL2-associated agonist of cell death) and BAX (BCL2-associated X protein) expression in MMG (Fig. 1 A). To exclude the possibility of contaminants in the gp120 preparation, we assessed the ability of gp120 to induce the release of pro-inflammatory TNF and immunosuppressive IL-10 from MMG following incubation with either a neutralising anti-gp120 antibody or 2-sulphanylethan-1-ol, which reduces disulphide bonds. Both treatments significantly reduced the release of TNF and IL-10 in response to gp120, without affecting LPS-mediated responses (Fig. 1 B). Furthermore, neutralising gp120 with specific antibodies completely abrogated the dose-dependent upregulation of TREM1 expression (Fig. 1 C). Fig. 1. Open in a new tab HIV Ba−L gp120 increases expression of BCL2, BCLXL, and TREM1 in microglia. A MMG were treated with gp120 or vehicle. After 24 h, cells were harvested and assayed for BCL2, BCLXL, BAX, BAD, and TREM1 expression. Left: representative western blots with ACTB as loading control. Right: densitometric analysis ( n = 4). B gp120 (2 ng mL⁻¹), LPS (100 ng mL⁻¹), or vehicle were pre-incubated for 1 h at 37 °C with 1 mM 2-sulphanylethan-1-ol (2-Me), 5 µg mL⁻¹ anti-gp120 antibody (VRC01), or 5 µg mL⁻¹ isotype control IgG. After 24 h treatment, TNF and IL-10 levels were quantified by ELISA ( n = 4). Dashed lines denote the assay limit of detection. C gp120 was pre-incubated with 5 µg mL⁻¹ VRC01 or isotype IgG for 1 h at 37 °C, then added to MMG. TREM1 expression was assessed by western blot at 24 h. Left: representative blots; right: densitometry ( n = 4). D MMG were transfected with TREM1 siRNA (si TREM1 ) or scrambled siRNA (siNS) for 48 h, followed by gp120 or vehicle treatment for 24 h. BCL2, BCLXL, BAX, BAD, and TREM1 were analysed by western blot. Left: representative western blots with ACTB as loading control; right: densitometry ( n = 4). The inset ‘% TREM remaining’ represents TREM1/ACTB densitometry expressed relative to the untreated siNS condition (set to 100%). E Cells from (D) were fixed, permeabilised, and assayed for apoptotic ssDNA by ELISA as a marker of apoptosis ( n = 4). F Supernatants from (D) were analysed for lactate dehydrogenase (LDH) activity as a marker of cytotoxicity ( n = 4). Individual data points represent biological replicates; bars indicate mean ± SD. * p < 0.05 To investigate whether the gp120-induced modulation of apoptotic pathways was dependent upon TREM1, we silenced TREM1 (Fig. 1 D). TREM1 -silenced MMG exposed to gp120 showed a significantly higher percentage of cells exhibiting apoptotic ssDNA (mean 83.3 ± 4.7% vs. 3.9 ± 0.1%; p = 0.00002; Fig. 1 E) and increased cytotoxicity (mean 79.7 ± 2.8% vs. 3.1 ± 1.6%; p = 0.00003; Fig. 1 F) across all donors compared to scrambled control-transfected cells. Moreover, TREM1 silencing abolished the gp120-induced upregulation of BCL2 and BCLXL, as well as the reduction in BAD and BAX expression (Fig. 1 D). These data indicate a functional contribution of TREM1 to the regulation of apoptotic and cytotoxic markers in gp120-exposed microglia. HIV gp120 upregulates TREM1 expression via activation of TLR2 and TLR4 Exposure of macrophages and/or microglia to LPS or HIV Tat has been shown to increase TREM1 expression through TLR-dependent signalling, particularly via TLR4 [ 70 – 72 ]. As gp120 can engage both TLR2- and TLR4-mediated innate immune pathways [ 30 , 32 , 73 ], we first examined the contribution of these receptors to gp120-mediated TREM1 upregulation in MMG using targeted receptor silencing (Fig. 2 A). Silencing either TLR2 or TLR4 alone partially attenuated gp120-induced increase in TREM1 expression, whereas combined silencing of both receptors resulted in an 85% (± 2.5%) reduction in TREM1 induction (two-way repeated-measures ANOVA with Bonferroni-corrected post-hoc test, p = 0.0002, Cohen’s d = 4.37), indicating synergistic or convergent signalling through these pathways. Because gp120 can engage the HIV co-receptor CCR5 in myeloid cells, we next assessed whether CCR5 contributes to gp120-induced TREM1 upregulation in MMG. Pharmacological antagonism of CCR5 with maraviroc reduced, but did not abolish, gp120-induced TREM1 expression in scrambled siRNA-transfected cells (Fig. 2 B). Maraviroc is an allosteric CCR5 antagonist that binds within a transmembrane pocket and stabilises a receptor conformation that alters gp120 recognition rather than competitively blocking ligand binding [ 74 , 75 ]. Under conditions of combined TLR2 and TLR4 silencing, residual TREM1 induction was further diminished by maraviroc, consistent with a modulatory rather than essential role for CCR5. To directly test whether CCR5 is required for gp120-induced TREM1 expression, CCR5 was silenced by siRNA (Fig. 2 C). Despite effective CCR5 silencing, gp120 exposure still induced robust TREM1 upregulation comparable to that observed in scrambled control cells, demonstrating that CCR5 is not required for gp120-mediated TREM1 induction under these conditions. Fig. 2. Open in a new tab HIV Ba−L gp120-mediated TREM1 expression in microglia is dependent on TLR2 and TLR4 but not CCR5. A MMG were transfected with siRNA targeting TLR2 (si TLR2 ), TLR4 (si TLR4 ), or scrambled control (siNS) for 48 h, then treated with gp120 or vehicle for 24 h. Left: representative western blots for TLR2, TLR4, and TREM1, with ACTB as loading control. Right: densitometric quantification ( n = 4). B MMG were transfected with scrambled siRNA (siNS) or combined siRNAs targeting TLR2 and TLR4 (si TLR2 & si TLR4 ) for 48 h, pretreated with maraviroc (10 nM) or vehicle for 1 h, and then exposed to gp120 (2 ng mL⁻¹) or vehicle for 24 h. TREM1 protein levels were assessed by western blot (left) and quantified by densitometry (right; n = 4). C MMG were transfected with scrambled siRNA (siNC) or siRNA targeting CCR5 (si CCR5 ) for 48 h, followed by exposure to gp120 (2 ng mL⁻¹) or vehicle for 24 h. Left: representative western blots for CCR5 and TREM1 with ACTB as loading control. Right: densitometric quantification confirming effective CCR5 knockdown and preserved gp120-induced TREM1 upregulation ( n = 4). TREM1 and ACTB in this panel were detected using antibody clones distinct from those used in other figures (see Methods). Data are shown as mean ± SD; * p < 0.05 HIV gp120-mediated TREM1 expression is dependent on PGE 2 synthesis Both LPS-induced TREM1 upregulation in macrophages and Tat-induced upregulation in microglia are dependent on the synthesis of PGE 2 from arachidonic acid by the enzymes prostaglandin-endoperoxide synthase (PTGS) 1 (previously cyclooxygenase-1 [COX-1]) and PTGS2 (previously COX-2), followed by conversion by prostaglandin E synthase 3 (PTGES3) or prostaglandin E synthase (PTGES) respectively [ 35 , 71 ]. As gp120 has been shown to induce PTGS2 expression in astrocytes [ 76 – 78 ], we investigated whether gp120 also upregulated PTGS enzymes and PGE 2 synthesis in MMG. Exposure of MMG to gp120 resulted in a dose-dependent increase in PTGS1, PTGS2, PTGES3, and PTGES expression (Fig. 3 A, B) and subsequent PGE 2 release (Fig. 3 C), which was completely abolished by the addition of a neutralising gp120 antibody (Fig. 3 D). Fig. 3. Open in a new tab HIV Ba−L gp120 induces PTGS2, PTGES, and PGE 2 expression in microglia. A – C MMG were treated with gp120 or vehicle. A At 6 h, cells were analysed for PTGS1 , PTGS2 , PTGES , and PTGES3 mRNA by RT-qPCR ( n = 4). B At 24 h, protein levels were assessed by western blot with ACTB as a loading control; left: representative blots, right: densitometric analysis ( n = 4). C Supernatants were collected and PGE₂ quantified by competitive enzyme immunoassay ( n = 4). D gp120 was pre-incubated with a neutralising antibody (VRC01; 5 µg mL⁻¹) or isotype control IgG (Iso IgG) for 1 h at 37 °C before being added to MMG. PGE₂ was quantified at 24 h ( n = 4). E MMG were transfected with siRNA targeting TLR2 (si TLR2 ), TLR4 (si TLR4 ), or scrambled siRNA (siNS) for 48 h, followed by treatment with gp120 or vehicle for 24 h. Left: representative western blots of PTGS1, PTGS2, PTGES, and PTGES3 with ACTB as a loading control. Right: densitometric analysis of blots ( n = 4). F Supernatants from ( E ) were analysed for PGE₂ content by competitive enzyme immunoassay ( n = 4). Data are shown as mean ± SD; * p < 0.05 To explore the role of TLR2 and TLR4 in the gp120-mediated synthesis of PGE 2 , we silenced both receptors (Fig. 3 E). Silencing TLR2 did not significantly alter the expression of PTGS1, PTGS2, or PTGES3, but it did reduce PTGES expression by 46% ( p = 0.0002), leading to a 27.3% reduction in PGE 2 release ( p = 0.013; Fig. 3 F). In contrast, TLR4 silencing significantly reduced the expression of PTGS1, PTGS2, and PTGES, resulting in a 74.4% decrease in PGE 2 release ( p = 0.003). Dual silencing of TLR2 and TLR4 further diminished PTGS1, PTGS2, and PTGES expression and reduced PGE 2 release by 95.5% ( p = 0.002). To determine whether the induction of TREM1 by gp120 was mediated through PGE 2 , we utilised specific inhibitors for PTGS1 (SC560) and PTGS2 (celecoxib). Celecoxib, but not SC560, significantly suppressed gp120-induced PGE 2 synthesis (Fig. 4 A) and TREM1 expression (Fig. 4 B and C). Additionally, inhibition of PTGES with MF63 abolished the gp120-mediated TREM1 expression (Fig. 4 D, E and F), suggesting that PGE 2 synthesis via PTGS2/PTGES is a key mediator of gp120-induced TREM1 expression. Importantly, vehicle-only controls confirmed that DMSO (≤ 0.1%) had no detectable effect on PGE₂ synthesis, TREM1 expression, or the expression of any upstream regulators assessed in these experiments. Temporal analysis revealed that the increase in PTGS2 expression and PGE 2 release occurred before the rise in TREM1 expression, with PTGS2 mRNA detectable within 5 min of gp120 exposure, PGE 2 release shortly thereafter, and TREM1 expression evident by 20 min (Fig. 4 G). Given prior reports that extracellular tryptophanyl-tRNA synthetase 1 (WARS1), an alarmin released by myeloid cells during infection or injury, can signal through TLR2 and TLR4 and induce TREM1 expression in myeloid cells [ 36 ], we assessed whether WARS1 release temporally aligned with the early PTGS2 and TREM1 mRNA induction observed after gp120 exposure. Extracellular WARS1 remained near baseline during the early window (0–20 min) and increased substantially only at later timepoints (1–24 h) (Fig. 4 H). WARS1 release did not temporally coincide with the initial induction of PTGS2 or TREM1 following gp120 exposure. Consistent with a PGE₂-mediated mechanism, direct exposure of MMG to PGE₂ resulted in a dose-dependent increase in expression (Fig. 4 I). To identify which prostaglandin E receptor (PTGER) mediates the TREM1-inducing effect of PGE 2 , we utilised PTGER antagonists. Antagonists for PTGER1, PTGER2, and PTGER3 had no detectable effect, indicating specific involvement of the PTGER4 receptor in TREM1 upregulation following PGE₂ stimulation (Fig. 4 J). These results suggest that the gp120-induced increase in TREM1 expression in MMG is dependent on PGE 2 synthesis via PTGS2 and PTGES, and that PGE 2 signalling through PTGER4 plays a key role in regulating gp120-induced TREM1 expression. Fig. 4. Open in a new tab HIV Ba−L gp120 induces PGE 2 expression in microglia via PTGS2 and PTGES. A–C MMG were pretreated with 10 nM SC560, 100 nM celecoxib, or vehicle for 1 h, then exposed to 2 ng mL⁻¹ gp120 or vehicle ( n = 4). A After 24 h, PGE₂ levels were measured by competitive immunoassay. B TREM1 mRNA was quantified at 6 h by RT-qPCR. C TREM1 protein was quantified at 24 h by western blot. Left: representative blots with ACTB as loading control. Right: densitometric analysis ( n = 4). D–F MMG were pretreated with 100 nM MF63 or vehicle for 1 h, then treated with gp120 or vehicle ( n = 4). D PGE₂ was measured at 24 h. E TREM1 protein was quantified at 24 h by western blot. Left: representative blots with ACTB as loading control. Right: densitometric analysis ( n = 4). G MMG were treated with gp120 or vehicle and harvested at multiple time points. PTGS2 and TREM1 mRNA were assessed by RT-qPCR, and PGE₂ by immunoassay ( n = 4). H Conditioned media were collected at early and late time points following gp120 or vehicle exposure and analysed for extracellular WARS1 by ELISA, with non-zero time points plotted on a log 10 time scale ( n = 4). I MMG were treated with PGE₂ or vehicle. TREM1 mRNA was measured at 6 h ( n = 4). J MMG were pretreated with 100 nM SC51322 (PTGER1/EP1 antagonist), 100 nM PF 04418948 (PTGER2/EP2 antagonist), 100 nM L-798,106 (PTGER3/EP3 antagonist), 100 nM E7046 (PTGER4/EP4 antagonist), or vehicle for 1 h before gp120 or vehicle exposure. TREM1 mRNA was quantified at 6 h by RT-qPCR ( n = 4). Data are shown as mean ± SD; * p < 0.05 HIV gp120-mediated TREM1 expression relies on Ca 2+ flux and NFATC1 activation The synthesis of PGE 2 requires the hydrolysis of phospholipids to arachidonic acid by cytosolic phospholipase A 2 α (cPLA 2 α), a process that is regulated by intracellular Ca 2+ signalling [ 79 ]. The expression of PTGS2 is similarly modulated by intracellular Ca 2+ through pathways involving the cAMP-response element-binding protein (CREB) and the calmodulin-dependent protein kinase II (CAMKII) and the calcineurin-NFAT pathways [ 80 – 83 ]. Given that gp120 induces a rapid influx of Ca 2+ in monocytes and macrophages [ 84 – 86 ], we investigated the role of Ca 2+ in the gp120-mediated induction of PTGS2, PGE 2 synthesis, and TREM1 expression. Pre-incubation with EGTA (ethylene glycol tetraacetic acid), which chelates extracellular Ca 2+ , prevented the gp120-induced expression of PTGS2, PTGES, and subsequent PGE 2 synthesis (Fig. 5 A, B and C). This resulted in the abrogation of TREM1 expression (Fig. 5 A and B) and a significant reduction in IL-10 production, with only a modest effect on TNF production (Fig. 5 D), confirming the dependency of the PTGS2/PGE₂/TREM1 axis on Ca 2+ flux. To further assess the role of CAMKII in the gp120-mediated increase in PTGS2 and PGE 2 , we used KN93, an inhibitor of Ca 2+ /calmodulin-dependent protein kinase II. KN93 effectively abolished the gp120-induced upregulation of PTGS2 and PTGES expression, as well as PGE 2 production (Fig. 6 A, B and C), without affecting TNF or IL-10 levels (Fig. 6 D). Fig. 5. Open in a new tab HIV Ba−L gp120-mediated TREM1 expression in microglia depends on Ca 2+ -regulated PGE 2 synthesis. MMG were pretreated with 2 mM EGTA or vehicle for 1 h before exposure to gp120 or vehicle ( n = 4). A After 6 h, cells were analysed for PTGS2 , PTGES , and TREM1 mRNA by RT-qPCR. B At 24 h, cells were harvested and analysed by western blot for PTGS2, PTGES, and TREM1; ACTB was used as a loading control. Left: representative blots. Right: densitometric analysis ( n = 4). C Supernatants were assessed for PGE₂ content by competitive enzyme immunoassay. D TNF and IL-10 release were quantified by ELISA; dashed lines indicate assay detection limits. Data are shown as mean ± SD; * p < 0.05 Fig. 6. Open in a new tab HIV Ba−L gp120-mediated TREM1 expression in microglia depends on CAMKII and calcineurin–NFAT signalling. A–D Monocyte-derived microglia (MMG) were pretreated with 10 ng mL⁻¹ tacrolimus, 1 µM KN93, or vehicle for 1 h, then treated with gp120 or vehicle ( n = 4). A After 6 h, cells were analysed for PTGS2 , PTGES , and TREM1 mRNA by RT-qPCR. B At 24 h, lysates were analysed by western blot for PTGS2, PTGES, and TREM1; ACTB was used as a loading control. Top: representative blots. Bottom: densitometric analysis ( n = 4). C Supernatants were assessed for PGE₂ by competitive enzyme immunoassay. D TNF and IL-10 were measured by ELISA; dashed lines indicate assay detection limits. E–F MMG were treated with gp120 or vehicle for 6 h. E Western blot analysis for Ser172-phosphorylated NFATC1, total NFATC1, and ACTB (loading control). Representative blots shown ( n = 4). F Cytoplasmic and nuclear fractions analysed for NFATC1, with ACTB (cytoplasmic) and H3C1 (nuclear) as loading controls. Representative blots shown ( n = 4). Data are shown as mean ± SD; * p < 0.05 We then investigated the involvement of the calcineurin-NFAT pathway. In response to an increase in intracellular Ca 2+ , calcineurin dephosphorylates NFAT proteins, leading to their translocation to the nucleus [ 87 , 88 ]. Upon gp120 exposure, nuclear factor of activated T cells 1 (NFATC1) was dephosphorylated (Fig. 6 E) and translocated to the nucleus (Fig. 6 F). Pre-incubation with tacrolimus, an inhibitor of calcineurin, significantly reduced the gp120-induced expression of PTGS2 (Fig. 6 A and B), and PGE 2 synthesis (Fig. 6 C), without affecting TNF or IL-10 production (Fig. 6 D). Finally, to confirm the role of NFATC1 in the gp120-mediated upregulation of PTGS2 and PGE 2 , we silenced NFATC1 (Fig. 7 A). NFATC1 silencing abrogated the gp120-induced expression of PTGS2 and PTGES, as well as PGE 2 synthesis, suggesting a critical role for NFATC1 in regulating TREM1 expression following gp120 exposure. Fig. 7. Open in a new tab HIV Ba−L gp120-mediated PGE 2 expression in microglia is independent of NF-κB. Monocyte-derived microglia (MMG) were transfected with RELA siRNA (si RELA ), NFATC1 siRNA (si NFATC1 ), or scrambled siRNA (siNS) for 48 h, followed by treatment with gp120 or vehicle for 24 h ( n = 4). A Left: representative western blots of RELA, NFATC1, TREM1, PTGS2, and PTGES with ACTB as a loading control. Right: densitometric analysis of blots. B Supernatants were analysed for PGE₂ by competitive enzyme immunoassay. Data are shown as mean ± SD Since NF-κB also regulates TREM1 expression in response to TLR4 signalling [ 69 – 71 , 89 ], we investigated whether NF-κB contributes to the gp120-mediated increase in TREM1 expression in MMG using RNAi for the NF-κB subunit RELA (Fig. 7 A). While RELA silencing significantly inhibited TREM1 expression (Fig. 7 B), it did not affect the gp120-mediated upregulation of PTGS2 or PTGES, or the synthesis of PGE 2 (Fig. 7 A and B). This suggests that although NF-κB is required for the expression of TREM1, the gp120-mediated increase in PTGS2 and PGE 2 , essential for TREM1 upregulation, is independent of NF-κB. Discussion The present study demonstrates that gp120 upregulates TREM1 expression in microglia (MMG) through TLR2 and TLR4 signalling pathways, with a mechanism that involves CAMKII and calcineurin, which regulate PTGS2-driven PGE 2 synthesis. Previous studies support this finding by demonstrating that gp120 signals through TLR2 and TLR4 [ 30 , 32 , 73 ]. A recent in vivo study further supports this mechanism, demonstrating that HIV-1 gp120 activates microglia through TLR2–NF-κB signalling to drive pro-inflammatory cytokine production and neuropathic pain [ 90 ]. Our data further extend these findings by demonstrating that this signalling cascade drives TREM1 expression and is associated with modulation of apoptotic and cytotoxic marker responses in gp120-exposed microglia. We previously demonstrated that Tat upregulates PTGS2, PTGES, PGE₂, and TREM1 in human microglia, establishing a PTGS2–PGE₂–TREM1 axis [ 71 ]. These data provided the rationale for focusing here on gp120 as a distinct viral input into the same pathway. Endogenous TLR ligands capable of signalling through TLR2 and TLR4 have been described in other systems [ 36 ]; whether such ligands contribute to gp120-associated signalling in microglia was not addressed in the present study. The potential contribution of Nef and other HIV-1 antigens to TREM1 regulation remains an important question for future investigation. PTGS2, a key enzyme involved in inflammation, is upregulated in response to gp120 exposure in MMG, and it is well known to mediate the production of PGE 2 , a potent pro-inflammatory mediator. In addition, PTGS2 activity has been linked to regulation of apoptotic signalling pathways in inflammatory contexts [ 91 , 92 ]. Our results show that gp120-induced PTGS2 overexpression in MMG is consistent with engagement of a PGE 2 -dependent pathway leading to TREM1 induction, and TREM1 expression is associated with modulation of apoptotic marker profiles following gp120 exposure. This is consistent with earlier work that demonstrated the protective effects of TREM1 in various inflammatory contexts [ 93 ]. TREM1 upregulation may influence the persistence of gp120-responsive microglial phenotypes by modulating inflammatory and apoptotic signalling pathways. Microglial activation and chronic neuroinflammation are hallmark features of HIV-associated neurocognitive disorders (HAND), as well as many other neurological diseases, including Alzheimer’s disease and Parkinson’s disease [ 94 , 95 ]. The persistent activation of microglia in the context of HIV infection can lead to the exacerbation of neuroinflammation, which in turn contributes to neuronal damage and cognitive decline. TREM1 has been shown to mediate the release of inflammatory cytokines and contribute to the amplification of immune responses in models of ischaemic stroke [ 96 , 97 ], subarachnoid haemorrhage [ 47 , 49 , 98 ], and other neurodegenerative conditions [ 45 , 99 , 100 ]. TREM1 silencing or blockade reduces mediator release and improves prognosis, supporting the potential for TREM1 inhibition as a therapeutic strategy for reducing neuroinflammation and enhancing recovery. Although we did not measure cytokine output after TREM1 silencing, previous work suggests that TREM1 amplifies TLR-induced cytokine release in myeloid cells, potentially exacerbating gp120-driven neuroinflammation. The role of TREM1 in viral infections, including HIV, is an area of growing interest. Although initially characterised in bacterial infections, viral signalling through pattern recognition receptors such as TLR3, TLR4, TLR7, and TLR8 has been shown to induce TREM1 expression in myeloid cells, including monocytes, macrophages, and microglia [ 38 , 70 , 71 ]. In the context of HIV, our data suggest that gp120-driven innate immune signalling engages TREM1 as part of a broader inflammatory amplification programme in microglia. PTGS2 and its downstream product PGE₂ have been implicated in HIV-associated neuroinflammation. In people living with HIV, elevated PTGS2 expression has been observed in brain-infiltrating macrophages during HIV encephalitis, and increased PGE₂ levels in serum and cerebrospinal fluid correlate with the severity of HIV-associated cognitive impairment [ 101 , 102 ]. In this context, our findings identify a gp120-driven PTGS2–PGE₂ signalling pathway in microglia that contributes to TREM1 upregulation and modulation of apoptotic and cytotoxic marker responses. These data provide a mechanistic framework linking viral protein–induced innate immune signalling to inflammatory pathways implicated in HIV-associated neurological dysfunction. We used an in vitro model of HIV exposure using monocyte-derived microglia, which enables controlled mechanistic interrogation but does not fully recapitulate the ontogeny, epigenetic programming, or cellular interactions of resident CNS microglia in vivo. Accordingly, baseline expression levels may differ in resident microglial populations, as may the magnitude or kinetics of gp120 responsiveness. In addition, recombinant gp120 was used to isolate viral protein-specific signalling pathways; while this approach allows precise dissection of upstream mechanisms, it does not capture the multifactorial signalling context of productive HIV infection or processes occurring outwith this experimental setting. Although all experiments were performed using primary MMG from independent donors and yielded qualitatively consistent responses, the limited sample size precluded formal assessment of inter-individual variability or potential influences of donor sex or age. Furthermore, while our data demonstrate that gp120-induced TREM1 expression is associated with modulation of apoptotic and cytotoxic marker responses, we did not examine downstream signalling events following TREM1 engagement or broader functional consequences such as cytokine release. Thus, the present findings support no more than a role for TREM1 in regulating apoptotic and cytotoxic pathways under these experimental conditions rather than definitive effects on long-term microglial survival. Future studies using complementary human or in vivo models will be required to determine how TREM1-dependent signalling influences microglial function in the context of chronic HIV infection. In conclusion, this study provides mechanistic insight into gp120-driven TLR2/TLR4–PGE₂ signalling that upregulates TREM1 in human monocyte-derived microglia, and links TREM1 expression to modulation of apoptotic and cytotoxic marker responses under these experimental conditions. Our findings suggest that TREM1 may represent a potential target for therapeutic modulation of gp120-exposed microglia and the attenuation of neuroinflammation within the CNS. Furthermore, the involvement of PTGS2 and PGE₂ in this regulatory cascade underscores the relevance of the PTGS2–PGE₂ to gp120-associated neuroinflammatory signalling. However, as TREM1 plays a role in coordinating host immune responses, complete inhibition could impair essential microglial functions. Therapeutic approaches should therefore aim to modulate, rather than abolish, TREM1 activity. Together, these findings advance understanding of innate immune signalling pathways engaged by HIV envelope proteins in microglia and provide a framework for future studies examining their role in neuroinflammation. Acknowledgements Not applicable. Abbreviations ALR AIM2-like receptor ART Antiretroviral therapy BAD BCL2-associated agonist of cell death BAX BCL2-associated X protein BCL2 B-cell lymphoma 2 BCLXL B-cell lymphoma-extra large CAMKII Calmodulin-dependent protein kinase cAMP Cyclic adenosine monophosphate CLR C-type lectin receptor cPLA₂α Cytosolic phospholipase A2α CNS Central nervous system CREB cAMP-response element-binding protein EGTA Ethylene glycol tetraacetic acid HAND HIV-associated neurocognitive disorders HIV Human immunodeficiency virus IL-10 Interleukin-10 LPS Lipopolysaccharide MMG Monocyte-derived microglia NFATC1 Nuclear factor of activated T cells 1 NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells NLR NOD-like receptor PAMP Pathogen-associated molecular pattern PGE₂ Prostaglandin E₂ PLWH People living with HIV PRR Pattern recognition receptor PTGER Prostaglandin E receptor PTGES Prostaglandin E synthase PTGS1 Prostaglandin-endoperoxide synthase 1 PTGS2 Prostaglandin-endoperoxide synthase 2 RELA NF-κB subunit RelA (p65) RLR RIG-I-like receptor Tat Trans-activator of transcription (HIV protein) TLR Toll-like receptor TNF Tumour necrosis factor TREM1 Triggering receptor expressed on myeloid cells 1 WARS1 Tryptophanyl-tRNA synthetase 1 Authors’ contributions GRC conceived and supervised the study. AM and GRC performed the experiments and analysed the data. PR and CT-D assisted with experimental design, contributed to data interpretation, supported analysis of microglial signalling pathways and experimental troubleshooting. GRC and SAS provided critical guidance and infrastructure support. AM and GRC wrote the manuscript with input from all authors. All authors read and approved the final manuscript. Funding This work was supported by the National Institute of Mental Health of the NIH (R01MH128021 to GRC), the National Institute of Neurological Disorders and Stroke of the NIH (R01NS104015 to SAS), the University of South Dakota Sanford School of Medicine (to GRC), and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network is provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Data availability All data generated or analysed during this study are included in this published article [and its supplementary information files]. Declarations Ethics approval and consent to participate Venous blood was collected from HIV-seronegative healthy volunteers (ages 18–65) at UC San Diego Health Sciences under a protocol approved by the Institutional Review Board (IRB) of the University of California, San Diego (approval number #180485AW), in accordance with the Code of Federal Regulations for the Protection of Human Subjects (45 CFR 46 and 21 CFR 50 and 56) and the principles of the Declaration of Helsinki. All participants provided written informed consent prior to participation; samples were fully de-identified and anonymised. Additional whole blood was obtained from the San Diego Blood Bank under an IRB exemption granted by the University of South Dakota Institutional Review Board (exemption number #IRB-22-209). De-identified samples were assigned to experimental conditions using simple randomisation. Consent for publication Not applicable. Competing interests The authors declare no competing interests. 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Data Availability Statement All data generated or analysed during this study are included in this published article [and its supplementary information files]. 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