bims-microg 2025-05-11 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–05–11
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions.
Nuclear Profilin-1 for DNA Damage Repair Is Involved in Phagocytic Impairment of Senescent Microglia.
Glucagon-Like Peptide 1 Receptor Agonist Stimulation Inhibits Laser-Induced Choroidal Neovascularization by Suppressing Intraocular Inflammation.
Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8+ T lymphocytes and aggravates spinal cord injury.
A Novel H2S Donor Alleviates Neuroinflammation and Seizures by Inhibiting the C3-C3aR Pathway.
Microglia positron emission tomography and progression in multiple sclerosis: thalamus on fire.
Reprogramming Retinal Microglia Polarization by Efferocytosis-Mimicking Nanoparticles for Ameliorating Diabetic Retinopathy.
Endoplasmic Reticulum Stress Drives Neuroinflammation Through Lipocalin 2 Upregulation in Retinal Microglia After Optic Nerve Injury.
Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica).
Drug screening targeting TREM2-TYROBP transmembrane binding.
Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway.
PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology.
OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ.
Gi signaling controls microglial surveillance and neuronal synchronization.
Loss of Plxdc2 exacerbates microglia-mediated neuroinflammation and ischemic brain injury.
In vitro models of microglia: a comparative study.
Microglia transcriptional states and their functional significance: Context drives diversity.
The Complementary Role of Morphology in Understanding Microglial Functional Heterogeneity.
TREM2 Impedes Recovery After Spinal Cord Injury by Regulating Microglial Lysosomal Membrane Permeabilization-Mediated Autophagy.
Evidence suggesting that microglia make amyloid from neuronally expressed APP: a hypothesis.

Cell Rep. 2025 May 06. pii: S2211-1247(25)00427-9. [Epub ahead of print]44(5): 115656

The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions.

Hyeji Jung, Byeongchan Kim, Gyubin Jang, Hyeonho Kim, Ae-Ree Lee, Sung-Hyun Yoon, Kyung-Seo Lee, Gaeun Hyun, Younghye Kim, Jaewon Ko, Je-Wook Yu, Ji Won Um.

  Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) conditional knockin (cKI) mice harboring a D301N point mutation originating in patients with autoinflammatory diseases, we found that activation of the NLRP3 inflammasome by administration of lipopolysaccharide induced anxiety-like and repetitive behaviors frequently found in patients with neuropsychiatric disorders, as well as increasing NMDAR (N-methyl-D-aspartate receptor)-mediated excitatory synaptic functions in the medial prefrontal cortex of mice. In addition, interleukin 1β (IL-1β), a downstream cytokine of the NLRP3 inflammasome, enhanced NMDAR activation and increased surface levels of the selective NMDAR subunit GluN2A in cultured cortical neurons. Strikingly, treatment with an NMDAR antagonist or IL-1 receptor antagonist completely normalized the specific behavioral deficits in Nlrp3D301N-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.

Keywords:  CP: Immunology; CP: Neuroscience; NLPR3; NMDAR; excitatory synapse; neuroinflammation; repetitive behavior

DOI:  https://doi.org/10.1016/j.celrep.2025.115656
Glia. 2025 May 03.

Nuclear Profilin-1 for DNA Damage Repair Is Involved in Phagocytic Impairment of Senescent Microglia.

Chan Rim, Soyoung Sung, Hui-Ju Kim, Seung Hyun Kim, Minyeop Nahm, Min-Soo Kwon.

  Accumulation of DNA damage is a hallmark of cellular senescence and plays a critical role in brain aging. Although the DNA damage repair mechanisms are crucial in cellular senescence, they are not well understood in microglia. In this study, we found that profilin-1 (PFN1), an actin-binding protein, relocates from the cytoplasm to the nucleus in response to DNA double-strand breaks (DSBs) induced by doxorubicin. This nuclear PFN1 subsequently translocates back to the cytoplasm during the recovery period. In response to DSBs, we detected enhanced expression of genes associated with nonhomologous end joining (NHEJ), but not with homologous recombination (HR), along with increased nuclear F-actin accumulation. However, this repair process is compromised when PFN1 is either knocked down or its nuclear transport is blocked. Notably, in DNA damage-induced senescent microglia, increased nuclear localization of PFN1 and nuclear F-actin formation are associated with phagocytic dysfunction. Both ex vivo aged microglia and publicly available single-cell RNA sequencing data from aged mouse brains recapitulate the in vitro findings described above. Despite cytochalasin D treatment for actin depolymerization, the return of PFN1 to the cytoplasm was not facilitated due to its aggregation. We propose that PFN1 plays an important role in DNA damage repair in microglia. In addition, the dysregulation of the nucleocytoplasmic balance of PFN1 alongside DNA damage accumulation may contribute to the phagocytic impairment of microglia in the aged brain.

Keywords:  DNA damage repair; Profilin‐1; phagocytosis; senescent microglia

DOI:  https://doi.org/10.1002/glia.70028
Invest Ophthalmol Vis Sci. 2025 May 01. 66(5): 15

Glucagon-Like Peptide 1 Receptor Agonist Stimulation Inhibits Laser-Induced Choroidal Neovascularization by Suppressing Intraocular Inflammation.

Akira Machida, Keiji Suzuki, Takafumi Nakayama, Sugao Miyagi, Yuki Maekawa, Ryuya Murakami, Masafumi Uematsu, Takashi Kitaoka, Akio Oishi.

Purpose: The glucagon-like peptide-1 receptor (GLP-1R), a diabetes therapy target, is expressed in multiple organs and is associated with neuroprotective, anti-inflammatory, and antitumor effects, particularly in cardiac and cerebral tissues. Although GLP-1's role in diabetic and ischemic retinopathies is well-studied, its influence on choroidal neovascularization (CNV) in exudative age-related macular degeneration (AMD) remains unclear. This study explored the effects of GLP-1 on CNV using a laser-induced mouse model.
Methods: The anti-angiogenic effects of GLP-1 were tested using ex vivo sprouting assays in 3-week-old C57BL/6J mice. In 6-week-old mice, GLP-1R localization in laser-induced CNV lesions was analyzed via immunohistochemistry. Liraglutide, a GLP-1R agonist, was administered subcutaneously for 7 days or by single intravitreal injection post-laser. Eyeballs collected on days 1 to 7 post-laser were analyzed using RT-qPCR for GLP-1R expression and inflammatory cytokines.
Results: GLP-1R-positive cells were detected in CNV lesions and were expressed in Iba-1-positive activated microglia or macrophages. They also expressed in abnormal retinal pigment epithelial cells and surrounding normal endothelial cells. NOD-like receptor protein 3 (NLRP3) inflammasome signaling was observed near CNV. Liraglutide inhibited angiogenesis in ex vivo assays and significantly reduced CNV formation with both subcutaneous and intravitreal administration. Additionally, Liraglutide inhibited expression of NLRP3, IL-1β, IL-6, and TNF expression compared with healthy controls. Intravitreal GLP-1R antagonist reduced subcutaneous effects.
Conclusions: Liraglutide suppresses CNV formation, likely via NLRP3 inflammasome inhibition. Intraocular GLP-1R appears to mediate anti-CNV effects, supporting GLP-1R agonists as potential adjunctive therapy for exudative AMD and warranting further investigation into its safety and clinical feasibility.

DOI: https://doi.org/10.1167/iovs.66.5.15
Neuron. 2025 Apr 24. pii: S0896-6273(25)00259-4. [Epub ahead of print]

Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8+ T lymphocytes and aggravates spinal cord injury.

Xuhui Ge, Yufeng Zhu, Junjun Xiong, Yao Gu, Xiaokun Wang, Wu Ye, Haofan Wang, Yu Gao, Weihua Cai, Xuhui Zhou, Wei Liu.

  Crosstalk between the central nervous system (CNS) and the immune system has recently gained increased attention; however, the interaction between innate and adaptive immunity after CNS injury remains unclear. Here, using single-cell RNA sequencing, we identified accumulation of CD8+ T lymphocytes in the cerebrospinal fluid of patients with spinal cord injury (SCI) and in spinal cords of injured mice, thus indicating poor neurological function. Furthermore, through genetic or pharmacologic interruption strategies, we found that CXCL16 chemokines derived from injury-activated microglia and macrophages (IAMs) recruited CXCR6+CD8+ T cells and further contributed to neuronal loss after SCI. Mechanistically, glycolytic reprogramming in IAMs enhanced histone-lactylation-mediated Cxcl16 transcription, whereas suppressing glycolysis through Pkm2 deletion partially reversed this effect. Notably, a pharmacologic intervention targeting the CXCL16-CXCR6 axis with Rutin promoted locomotor restoration after SCI. Our study highlights the crucial role of glycolytically reprogrammed IAM-derived CXCL16 chemokines in modulating a maladaptive innate/adaptive immune axis and reveals several potential therapeutic strategies.

Keywords:  CD8+ T lymphocytes; CXCL16; adaptive immunity; histone lactylation; metabolic reprogramming; microglia and macrophages

DOI:  https://doi.org/10.1016/j.neuron.2025.04.003
J Neurosci Res. 2025 May;103(5): e70041

A Novel H2S Donor Alleviates Neuroinflammation and Seizures by Inhibiting the C3-C3aR Pathway.

Yaru Yang, Xutao Wang, Tiantian Wang, Xiao Wang, Honghao Xu, Lian Liu, Shuisheng Lei, Xiao Qin Zhu.

  Both astrocytes and microglia are activated in the epileptic brain. There is an interaction between them through the complement 3 (C3)-C3a receptor (C3aR) pathway, which plays a detrimental role in seizures. Our self-developed novel H2S donor has been found to have anti-seizure effects. However, its mechanism remains to be explored. In the present study, we showed that the novel H2S donor can inhibit the activation of astrocytes and microglia and their interaction through C3-C3aR signaling, which contributed to alleviating microglial neuroinflammation and seizures. In LPS-treated astrocytes and pilocarpine-induced epileptic mice, the H2S donor reduced C3 production in astrocytes and regulated the expression of inflammatory cytokines IL-1β and IL-10 in microglia. The H2S donor also reduced the EEG amplitude of hippocampal epileptic waves and relieved seizures in epileptic mice. These effects of the H2S donor can be reversed by intranasal C3 treatment and mimicked by a C3aR antagonist. These findings provide a novel mechanism underlying the anti-seizure effects of the H2S donor. Therefore, the H2S donor has the potential to be used as a candidate for antiepileptic drugs.

Keywords:  C3‐C3aR pathway; H2S; astrocyte; epilepsy; microglia

DOI:  https://doi.org/10.1002/jnr.70041
Brain Commun. 2025 ;7(3): fcaf141

Microglia positron emission tomography and progression in multiple sclerosis: thalamus on fire.

Burcu Zeydan, Nur Neyal, Jiye Son, Christopher G Schwarz, June C Kendall Thomas, Holly A Morrison, Melissa L Bush, Robert I Reid, Scott A Przybelski, Angela J Fought, Clifford R Jack, Ronald C Petersen, Kejal Kantarci, Val J Lowe, Laura Airas, Orhun H Kantarci.

  Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, 11C-ER176, and investigate the associations of 11C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis (n = 50) and controls (n = 55) were prospectively enrolled and they underwent 11C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging. Disease characteristics, expanded disability status scale and multiple sclerosis functional composite scores were obtained in patients with multiple sclerosis. Age at imaging (mean ± standard deviation: patients = 49.6 ± 12.9 years, controls = 48.2 ± 15.4 years, P = 0.63) and sex (female ratio; patients = 72%, controls = 65%, P = 0.47) were not different between the groups. Thalamus 11C-ER176 PET uptake was highest in patients with progressive multiple sclerosis (1.272 ± 0.072 standardized uptake value ratio), followed by patients with relapsing multiple sclerosis (1.209 ± 0.074 standardized uptake value ratio) and lowest in controls (1.162 ± 0.067 standardized uptake value ratio, P < 0.001). Patients with thalamic lesions had higher thalamus 11C-ER176 PET uptake than those without thalamic lesions in both relapsing multiple sclerosis and progressive multiple sclerosis (P < 0.001). In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with lower thalamic volume (r = -0.45, P = 0.001), higher mean diffusivity (r = 0.56, P < 0.001), lower neurite density index (r = -0.43, P = 0.002), lower orientation dispersion index (r = -0.40, P = 0.005) and higher free water fraction (r = 0.42, P = 0.003) in the thalamus. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake also correlated with higher mean diffusivity (r = 0.47, P < 0.001) and lower neurite density index (r = -0.36, P = 0.012) in the corpus callosum. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with worse expanded disability status scale scores (r = 0.33, P = 0.02), paced auditory serial addition test scores (r = -0.43, P = 0.003) and multiple sclerosis functional composite z-scores (r = -0.46, P = 0.001). Microglia density in the thalamus is highest in patients with progressive multiple sclerosis and is associated with imaging biomarkers of neurodegeneration and clinical disease severity. As a signature imaging biomarker of progression in multiple sclerosis, effectively reflecting the global disease burden, 11C-ER176 PET may aid development and efficacy evaluation of therapeutics targeting microglia.

Keywords:  11C-ER176 positron emission tomography; magnetic resonance imaging; microglia; multiple sclerosis; thalamus

DOI:  https://doi.org/10.1093/braincomms/fcaf141
ACS Appl Mater Interfaces. 2025 May 07.

Reprogramming Retinal Microglia Polarization by Efferocytosis-Mimicking Nanoparticles for Ameliorating Diabetic Retinopathy.

Zhipeng Li, Wenyu Wang, Liping Zhu, Zhiqiang Wang, Chaolong Liu, Yong Sun, Jingliang Wu, Qing Wang.

  Diabetic retinopathy (DR), as the most common microvascular complication of diabetes, seriously threatens the vision of diabetic patients. As the resident phagocytes of the retina, microglia participate in inflammation, neovascularization, and neurodegeneration of DR. Herein, apoptotic retinal cell membrane-coated, rapamycin-loaded mesoporous Prussian blue NPs as immunomodulators for ameliorating DR by modulating microglial polarization are reported. The apoM@mPB@Ra NPs exhibited favorable stability and biocompatibility and achieved active targeted delivery due to the specific recognition between "eat me" signal expressed on apoptotic membrane and microglia. In an LPS-induced cellular inflammation model, apoM@mPB@Ra NPs effectively promoted microglial polarization toward the anti-inflammatory phenotype (M2) by scavenging intracellular reactive oxygen species (ROS) combined with affecting the mTOR signaling pathway, leading to downregulation of pro-inflammatory cytokines IL-6 and TNF-α. Meanwhile, owing to the multienzyme-like activities of mPB in nanoparticles, apoM@mPB@Ra NPs obviously alleviated cellular hypoxia, thereby decreasing the expression of VEGF. Notably, in a mouse model of DR, intravitreally injected apoM@mPB@Ra NPs significantly improved the severity of the abnormal retinal vascular network and inflammatory microenvironment of retinopathy by down-regulating the expression of HIF-1α, VEGF, and inflammatory-related cytokines. Collectively, these findings demonstrate that apoM@mPB@Ra NPs provide a promising and effective approach for the treatment of DR.

Keywords:  apoptotic membrane; diabetic retinopathy; microglial polarization; prussian blue nanoparticles; reactive oxygen species

DOI:  https://doi.org/10.1021/acsami.5c03170
Invest Ophthalmol Vis Sci. 2025 May 01. 66(5): 12

Endoplasmic Reticulum Stress Drives Neuroinflammation Through Lipocalin 2 Upregulation in Retinal Microglia After Optic Nerve Injury.

Weifeng Huang, Yaoming Liu, Jinmiao Li, Yang Gao, Junjie Tang, Siuhang Yip, Xinyue Wang, Hongwei Zhang, Yujun Ma, Shicai Su, Jiahe Nie, Rong Lu.

Purpose: This study aims to explore how lipocalin 2 (LCN2) connects endoplasmic reticulum (ER) stress and inflammation in optic nerve injury (ONI) and identify potential therapeutic strategies.
Methods: An optic nerve crush (ONC) mouse model was used to investigate the role of ER stress and LCN2 in ONI. Immunofluorescence, quantitative PCR, and Western blot analyses were performed to assess ER stress markers, LCN2, inflammation-related genes, and retinal ganglion cell (RGC) survival, with or without treatment of 4PBA (an ER stress inhibitor) and TUN (an ER stress activator) in both the ONC model and BV2 cells. Lcn2 knockdown was achieved using small interfering RNA in BV2 cells and adeno-associated virus (AAV)-mediated gene silencing in vivo to explore underlying signaling pathways.
Results: ER stress markers (GRP78, ATF4, CHOP) and LCN2 expression were increased in ONC retinas, accompanied by microglial activation and RGC loss. Inhibition of ER stress using 4PBA effectively decreased LCN2 expression, attenuated microglial activation, and increased RGC survival post-ONC. Intravitreal injection of recombinant LCN2 induced a proinflammatory phenotype in microglia and exacerbated neurotoxicity. AAV-mediated Lcn2 silencing mitigated microglial activation, reduced neuroinflammation, and provided RGC neuroprotection, surpassing 4PBA treatment. In vitro studies further confirmed that Lcn2 knockdown significantly reduced the inflammatory response in BV2 cells by inhibiting NLRP3 inflammasome activation via the TLR4/NF-κB pathway.
Conclusions: This study elucidates the critical role of LCN2 in linking ER stress and inflammation in ONI, offering a promising therapeutic target. AAV-mediated Lcn2 silencing outperforms broad ER stress inhibition, providing a novel strategy for treating optic nerve injuries.

DOI: https://doi.org/10.1167/iovs.66.5.12
Int J Mol Sci. 2025 Apr 10. pii: 3585. [Epub ahead of print]26(8):

Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica).

Ryo Yamasaki.

  Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder.

Keywords:  complement inhibition; macrophage; microglia; multiple sclerosis; neuroinflammation; neuromyelitis optica spectrum disorder; remyelination; therapeutic modulation

DOI:  https://doi.org/10.3390/ijms26083585
Mol Med. 2025 May 05. 31(1): 171

Drug screening targeting TREM2-TYROBP transmembrane binding.

M Cobas-Carreño, A Esteban-Martos, L Tomas-Gallardo, I Iribarren, L Gonzalez-Palma, A Rivera-Ramos, J Elena-Guerra, E Alarcon-Martin, R Ruiz, M J Bravo, J L Venero, X Morató, A Ruiz, J L Royo.

  TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimer's disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.

Keywords:  B2H; BATCH; DAP12; Drug screening; TREM2; TYROBP; Varenicline

DOI:  https://doi.org/10.1186/s10020-025-01229-y
Open Med (Wars). 2025 ;20(1): 20251182

Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway.

Lan-Lan Liu, Xin Liu, Shuang Zhao, Zhao Li, Jia-Xin Liu, Dong-Yang Ma, Xiu-Li Wang.

   Background: Paclitaxel (PTX) chemotherapy frequently induces cognitive impairment, which is closely associated with two key pathological processes: necroptosis of hippocampal neurons and microglial polarization. Necroptotic neurons release damage-associated molecular patterns, triggering inflammatory responses. As the primary immune cells in the central nervous system, microglia can exhibit either pro-inflammatory or anti-inflammatory activity depending on their polarization state. However, the relationship between PTX-induced neuronal necroptosis and microglial activation remains unclear.
Methods: In this study, both in vivo and in vitro experiments were conducted. In vivo, an adult male C57BL/6N mouse model of PTX-induced cognitive impairment was established and divided into three groups: Veh (vehicle control), PTX (paclitaxel only), and P + N (paclitaxel with Nec-1 treatment). Necrostatin-1 (Nec-1), a specific inhibitor of RIPK1, was used to inhibit necroptosis. In vitro, HT22 cells were used to prepare necroptosis-conditioned medium, and BV-2 cells were treated with this medium. TAK-242, a TLR4 inhibitor, was used to explore the role of the TLR4/MyD88 signaling pathway. Immunofluorescence staining, western blot, and ELISA were employed to detect relevant markers and cytokines.
Results: The results demonstrated that PTX-induced necroptosis of hippocampal neurons activated microglia. Nec-1 effectively suppressed neuronal necroptosis and reduced M1 polarization of microglia. The TLR4/MyD88 signaling pathway was involved in microglial polarization induced by the necroptotic-conditioned medium of PTX-treated HT22 cells. TAK-242 significantly blocked the regulatory effect of PTX-induced neuronal necroptosis on BV-2 microglial polarization.
Conclusion: This study reveals that hippocampal neuron necroptosis activates microglia through the TLR4/MyD88 signaling pathway in PTX-induced cognitive impairment, promoting M1 polarization and neuroinflammation. Inhibiting necroptosis promotes M2 polarization and neuroprotection. These findings uncover a novel mechanism of PTX-induced cognitive impairment and suggest potential therapeutic targets.

Keywords:  DAMPs; TLR4/MyD88 signaling pathway; microglia polarization; necroptosis; paclitaxel

DOI:  https://doi.org/10.1515/med-2025-1182
Alzheimers Dement. 2025 May;21(5): e70231

PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology.

Evan J Messenger, Sydney A Baar, Logan M Bedford, Andy P Tsai, Peter Bor-Chian Lin, Chloe A Ferguson, Guixiang Xu, Abigail Wallace, Gary E Landreth, Bruce T Lamb, Stephanie J Bissel.

   BACKGROUND: Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2). Variants which alter PLCG2 activity impact Alzheimer's disease (AD) risk, but the effects of PLCG2 deficiency in AD remain unclear.
METHODS: 5xFAD mice were crossed with PLCG2- and TREM2-deficient mice to assess the role of PLCG2 in response to amyloid pathology. Human bulk RNA-sequencing data were used to validate findings in AD patients.
RESULTS: In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques. Transcriptomic analysis revealed perturbations in immune-related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences. Human transcriptomics revealed positive correlations between PLCG2 and TREM2 independent of pathological scores.
DISCUSSION: PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation. These findings clarify the mechanisms of risk and protective PLCG2 variants.
HIGHLIGHTS: The role of phospholipase C gamma 2 (PLCG2) deficiency in response to amyloid beta (Aβ) pathology was investigated in 5xFAD mice and with human cortical transcriptomics. PLCG2 deficiency significantly reduces triggering receptor expressed on myeloid cells 2 (TREM2) expression, while TREM2 deficiency increases PLCG2 expression. PLCG2 expression predicts TREM2 expression in human cortex independent of pathology. PLCG2 and TREM2 deficiencies similarly impair microglial responses to Aβ plaques, exacerbate neuronal pathology, and impair gene expression associated with immune responses. PLCG2 deficiency confers distinct transcriptional perturbations from TREM2 deficiency. PLCG2 may play an upstream role in the regulation of the TREM2-mediated immune response.

Keywords:  5xFAD; Alzheimer's disease; amyloid pathology; immune response; microglia; phospholipase C gamma 2; triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1002/alz.70231
Acta Pharmacol Sin. 2025 May 07.

OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ.

Ling-Yu She, Lu-Yao Li, Hao Tang, Qin Yu, Feng-Yi Gao, Yu-Qing Zeng, Lin-Jie Chen, Li Xiong, Li-Wei Li, Fan Chen, Jin-Feng Sun, Wen-Hua Zheng, Xia Zhao, Guang Liang.

  Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Microglia-mediated neuroinflammation is closely associated with AD pathogenesis. Abnormal deubiquitinating enzyme (DUB) expression is associated with neuroinflammation. Identification of functional DUBs in microglia may provide novel targets for AD treatment. Here, we found that the levels of DUB, ovarian tumor deubiquitinase 1 (OTUD1), were upregulated in AD model mice and amyloid-beta-induced microglia. OTUD1 knockdown in microglia significantly inhibited neuroinflammation, thereby improving cognitive impairment in AD model mice. Liquid chromatography-tandem mass spectrometry analysis coupled with co-immunoprecipitation revealed the CCAAT/enhancer-binding protein β (C/EBPβ), a key transcription factor regulating microglial inflammation, as an OTUD1-interacting protein. Mechanistically, OTUD1 bound to C/EBPβ and maintained its stability by removing the K48 ubiquitin chain at K253 of C/EBPβ, thereby activating the C/EBPβ-nuclear factor-κB-mediated inflammatory responses in microglia. Overall, our results revealed the roles of the OTUD1-C/EBPβ axis in mediating the microglial inflammatory responses and AD pathology, facilitating the development of new strategies targeting microglial neuroinflammation for AD treatment.

Keywords:  Alzheimer’s disease; C/EBPβ; OTUD1; microglia; neuroinflammation

DOI:  https://doi.org/10.1038/s41401-025-01566-y
Trends Neurosci. 2025 May 08. pii: S0166-2236(25)00081-5. [Epub ahead of print]

Gi signaling controls microglial surveillance and neuronal synchronization.

Aletta M R van den Bosch, Jörg Hamann.

  Microglia-neuron interactions are essential for maintaining brain homeostasis. In a recent study, Zhao and colleagues demonstrated that activation of Gi-G-protein-coupled receptors (Gi-GPCRs) on microglia suppresses microglial process dynamics, reduces neuronal activity, and disrupts network synchronization. These findings highlight the role of microglial Gi-GPCR signaling in neuromodulation and its role in network activity in the healthy brain.

Keywords:  CNS; GPCR; glia; homeostasis; neuroimmune; neuronal network

DOI:  https://doi.org/10.1016/j.tins.2025.04.006
Exp Neurol. 2025 May 07. pii: S0014-4886(25)00166-9. [Epub ahead of print] 115302

Loss of Plxdc2 exacerbates microglia-mediated neuroinflammation and ischemic brain injury.

Lixuan Yang, Yang Geng, Yi Qian, Ningning Zong, Shengnan Xia, Haiyan Yang, Xinyu Bao, Jian Chen, Yun Xu.

  Microglia are the supervisors maintaining intracerebral homeostasis, which function importantly in determining the outcome of ischemic stroke. Plxdc2 is a single-transmembrane protein and mainly studied in the development of central nervous system and cancers, whereas its role in the function of microglia remains elusive. In this study, based on our previous scRNA-seq of ischemic brain and transcriptomic analysis of microglia isolated from the ischemic brain, we found that Plxdc2 was abundantly expressed in microglia and remarkably downregulated after stroke. Further, with adeno-associated virus (AAV) overexpressing or lentivirus interfering Plxdc2 in microglia in vivo, Plxdc2 was proved to protect against ischemic brain injury. Plxdc2 helps maintain microglial homeostatic state both in vitro and in vivo, and downregulation of Plxdc2 exacerbated microglial inflammatory response. In addition, we found that Plxdc2 participated in regulating the activation of NF-κB p65 signaling, and also modulated microglial lipid metabolism. Moreover, Plxdc2 was found to facilitate the activation of PPARγ, which might account for its impact on NF-κB p65 signaling and lipid metabolism in microglia. Overall, our results illustrated a vital role of Plxdc2 in modulating post-stroke microglial activation, which holds potential to be a novel target for immunomodulation in ischemic stroke.

Keywords:  Ischemic stroke; Microglia; Plxdc2

DOI:  https://doi.org/10.1016/j.expneurol.2025.115302
Sci Rep. 2025 May 05. 15(1): 15621

In vitro models of microglia: a comparative study.

Zoe Woolf, Taylor J Stevenson, Kevin Lee, Blake Highet, Jena Macapagal Foliaki, Ramona Ratiu, Justin Rustenhoven, Jason Correia, Patrick Schweder, Peter Heppner, Maria Weinert, Natacha Coppieters, Thomas Park, Johanna Montgomery, Amy M Smith, Michael Dragunow.

  Microglia perform key homeostatic functions to protect the central nervous system (CNS). However, in many brain disorders their protective functions are abrogated, contributing to disease progression. Therefore, studies of microglial function are critical to developing treatments for brain disorders. Different in vitro microglia models have been established, including primary human and rodent cells, induced pluripotent stem cell (iPSC)-derived models, and immortalised cell lines. However, a direct comparative analysis of the phenotypic and functional characteristics of these models has not been undertaken. Accurate modelling of human microglia in vitro is critical for ensuring the translatability of results from the bench to the brain. Therefore, our study aimed to characterise and compare commonly utilised in vitro microglia models. We assessed four established microglia models: primary human microglia, human iPSC-derived microglia, the human microglial clone 3 (HMC3) cell line, and primary mouse microglia, with primary human brain pericytes acting as a negative control. Primary human microglia, iPSC-derived microglia, and mouse microglia stained positive for myeloid-cell markers (Iba1, CD45 and PU.1), while HMC3 cells only stained positive for mural-cell markers (PDGFRβ and NG2). Distinct secretomes were observed in all cell models in response to inflammatory treatment, with iPSC-derived microglia showing the most significant inflammatory secretions. Notably, nitric oxide was only secreted by mouse microglia. Although all cell types exhibited phagocytic capacity, primary human microglia and iPSC-derived microglia displayed significantly higher levels of phagocytosis. Overall, comparative analysis revealed notable differences between human microglia, iPSC-derived microglia, HMC3 cells and mouse microglia. Such differences should be considered when using these models to study human brain diseases. Experimental findings obtained from mouse models or cell lines should ultimately be cross validated to ensure the translatability of results to the human condition.

Keywords:   In vitro models; Comparative analysis; Human microglial clone 3 (HMC3); Microglia; iPSC-derived microglia

DOI:  https://doi.org/10.1038/s41598-025-99867-z
Immunity. 2025 May 05. pii: S1074-7613(25)00172-4. [Epub ahead of print]

Microglia transcriptional states and their functional significance: Context drives diversity.

Constanze Depp, Jordan L Doman, Maximilian Hingerl, Judy Xia, Beth Stevens.

  In the brain, microglia are continuously exposed to a dynamic microenvironment throughout life, requiring them to adapt accordingly to specific developmental or disease-related demands. The advent of single-cell sequencing technologies has revealed the diversity of microglial transcriptional states. In this review, we explore the various contexts that drive transcriptional diversity in microglia and assess the extent to which non-homeostatic conditions induce context-specific signatures. We discuss our current understanding and knowledge gaps regarding the relationship between transcriptional states and microglial function, review the influence of complex microenvironments and prior experiences on microglial state induction, and highlight strategies to bridge the gap between mouse and human studies to advance microglia-targeting therapeutics.

Keywords:  disease-associated microglia; iPSC-derived microglia; microglia; microglia signature; microglia states; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.immuni.2025.04.009
Int J Mol Sci. 2025 Apr 17. pii: 3811. [Epub ahead of print]26(8):

The Complementary Role of Morphology in Understanding Microglial Functional Heterogeneity.

Sânziana Godeanu, Bogdan Cătălin.

  A search of the PubMed database for publications on microglia reveals an intriguing shift in scientific interest over time. Dividing microglia into categories such as "resting" and "activated" or M1 versus M2 is nowadays obsolete, with the current research focusing on unraveling microglial heterogeneity. The onset of transcriptomics, especially single-cell RNA sequencing (scRNA-seq), has profoundly reshaped our understanding of microglia heterogeneity. Conversely, microglia morphology analysis can offer important insights regarding their activation state or involvement in tissue responses. This review explores microglial heterogeneity under homeostatic conditions, developmental stages, and disease states, with a focus on integrating transcriptomic data with morphological analysis. Beyond the core gene expression profile, regional differences are observed with cerebellar microglia exhibiting a uniquely immune-vigilant profile. During development, microglia express homeostatic genes before birth, yet the bushy appearance is a characteristic that appears later on. In neurodegeneration, microglia alternate between proinflammatory and neuroprotective roles, influenced by regional factors and disease onset. Understanding these structural adaptations may help identify specific microglial subpopulations for targeted therapeutic strategies.

Keywords:  heterogeneity; microglia; morphology; transcriptomics

DOI:  https://doi.org/10.3390/ijms26083811
Cell Prolif. 2025 May 04. e70047

TREM2 Impedes Recovery After Spinal Cord Injury by Regulating Microglial Lysosomal Membrane Permeabilization-Mediated Autophagy.

Tianlun Zhao, Jiawei Di, Yu Kang, Haojie Zhang, Senyu Yao, Bin Liu, Limin Rong.

  Microglia, considered as the main immune responder, play an important role in regulating neuroinflammation in central nervous system (CNS) disorders. Our previous work found that TREM2 is highly expressed in microglia and is related to their functional state. However, the specific role of TREM2 in spinal cord injury has not yet been explored. To further investigate the potential mechanism of TREM2, we performed single-cell sequencing on wild-type (Wt) and Trem2-/- mice before and after spinal cord injury. Compared to Wt mice, the lysosome, autophagy and membrane-related pathways are more strongly activated in Trem2-/- mice, suggesting that TREM2 may exert its effects by influencing lysosomal membranes and autophagy. Mechanistically, we demonstrated that the knockout of Trem2 can reduce the nuclear translocation of TFEB by decreasing the phosphorylation of Syk. Furthermore, we validated that in vitro and in vivo silencing Trem2 can promote autophagy by repairing lysosomal membrane permeabilization. Through immunofluorescence, 3D gait analysis, motor evoked potential experiments, H&E staining and Masson staining, we demonstrated that the increased level of autophagy can rescue more microglia in vivo and promote both functional and histological recovery of spinal cord injury. Collectively, these results not only suggest that microglial lysosomal autophagy is regulated in a TREM2-dependent LMP manner, but also, more importantly, they provide a promising clinical translation strategy based on gene therapy for lysosome-related central nervous system disorders.

Keywords:  TREM2; autophagy; lysosomal membrane permeabilization; microglia; spinal cord injury

DOI:  https://doi.org/10.1111/cpr.70047
Mol Neurodegener. 2025 May 09. 20(1): 55

Evidence suggesting that microglia make amyloid from neuronally expressed APP: a hypothesis.

John Hardy, Patrick Lewis.

While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.

DOI: https://doi.org/10.1186/s13024-025-00847-8