bims-microg 2025-02-09 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–02–09
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Divergent sex-specific pannexin-1 mechanisms in microglia and T cells underlie neuropathic pain.
Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model.
Microglial C/EBPβ-Fcgr1 regulatory axis blocking inhibits microglial pyroptosis and improves neurological recovery.
Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.
Exploratory analysis of a Novel RACK1 mutation and its potential role in epileptic seizures via Microglia activation.
Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases.
Inhibiting HMGB1/AGER/NF-κB pathway prevents pro-inflammatory microglia polarization and protect photoreceptors in retinitis pigmentosa.
Dapagliflozin alleviated seizures and cognition impairment in pilocarpine induced status epilepticus via suppressing microglia-mediated neuroinflammation and oxidative stress.
NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.
GPx3 Promotes Functional Recovery after Spinal Cord Injury by Inhibiting Microglial Pyroptosis Through IRAK4/ROS/NLRP3 Axis.
A mathematical model of microglia glucose metabolism and lactylation with positive feedback.
Derivation of a Human Brain Organoid with Microglia Development.
Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology.
A ketogenic diet regulates microglial activation to treat drug addiction.
CD22 modulation alleviates amyloid β-induced neuroinflammation.
Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.
CNS resident macrophages exhibit region-specific states and immunogenic responses during Rbpj-deficient brain arteriovenous malformation.
Interneuron loss and microglia activation by transcriptome analyses in the basal ganglia of Tourette disorder.
Allopregnanolone relieves paclitaxel induced mechanical hypersensitivity via inhibiting spinal cord PGE2-EP2 mediated microglia-neuron signaling.

Neuron. 2025 Jan 29. pii: S0896-6273(25)00009-1. [Epub ahead of print]

Divergent sex-specific pannexin-1 mechanisms in microglia and T cells underlie neuropathic pain.

Churmy Y Fan, Brendan B McAllister, Sierra Stokes-Heck, Erika K Harding, Aliny Pereira de Vasconcelos, Laura K Mah, Lucas V Lima, Nynke J van den Hoogen, Sarah F Rosen, Boram Ham, Zizhen Zhang, Hongrui Liu, Franz J Zemp, Regula Burkhard, Markus B Geuking, Douglas J Mahoney, Gerald W Zamponi, Jeffrey S Mogil, Shalina S Ousman, Tuan Trang.

  Chronic pain is a leading cause of disability, affecting more women than men. Different immune cells contribute to this sexual divergence, but the mechanisms, especially in females, are not well defined. We show that pannexin-1 (Panx1) channels on microglia and T cells differentially cause mechanical allodynia, a debilitating symptom of neuropathic pain. In male rodents, Panx1 drives vascular endothelial growth factor-A (VEGF-A) release from microglia. Cell-specific knockdown of microglial Panx1 or pharmacological blockade of the VEGF receptor attenuated allodynia in nerve-injured males. In females, nerve injury increased spinal CD8+ T cells and leptin levels. Leptin release from female-derived CD8+ T cells was Panx1 dependent, and intrathecal leptin-neutralizing antibody injection sex-specifically reversed allodynia. Adoptive transfer of female-derived CD8+ T cells caused robust allodynia, which was prevented by a leptin-neutralizing antibody or leptin small interfering RNA (siRNA) knockdown. Panx1-targeted approaches may alleviate neuropathic pain in both sexes, while T cell- and leptin-directed treatments could have sex-dependent benefits for women.

Keywords:  Neuropathic pain; Pannexin-1; T cells; VEGF; allodynia; leptin; microglia; nerve injury; sex differences; spinal cord

DOI:  https://doi.org/10.1016/j.neuron.2025.01.005
Sci Adv. 2025 Feb 07. 11(6): eadq6038

Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model.

Xiaoting Wu, James Alastair Miller, Bernett Teck Kwong Lee, Yulan Wang, Christiane Ruedl.

Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer's disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c+ microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1+ brain macrophages using an inducible APP-KI/Fit2iΔMφ transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1+ BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.

DOI: https://doi.org/10.1126/sciadv.adq6038
J Neuroinflammation. 2025 Jan 31. 22(1): 29

Microglial C/EBPβ-Fcgr1 regulatory axis blocking inhibits microglial pyroptosis and improves neurological recovery.

Jing Li, Yubing Yang, Chenguang Zhao, Jinghao Zhao, Xiaohui Wang, Shengshou Ye, Dong Wang, Chengdong Zhou, Jie Li, Shuang Wang, Ke Li, Chunmiao Liu, Xijing He, Jie Qin.

  CAAT/Enhancer Binding Protein β (C/EBPβ) is associated with inflammatory responses in neurodegenerative pathologies, particularly in the brain. However, the regulatory role of C/EBPβ in spinal cord injury and its impact on neurological recovery remain unknown. In this study, we observed significant upregulation of C/EBPβ in microglia after spinal cord injury in mice and was associated with neuroinflammation. Knocking down C/EBPβ in the spinal cord attenuated microglia pyroptosis, reduced the production of proinflammatory cytokines, and inhibited neuronal apoptosis. Mechanistically, C/EBPβ promoted the transcription of Fcgr1, which was involved in activating microglia pyroptosis. In both in-vivo and in-vitro experiments, knocking down Cebpb or Fcgr1, or the pyroptosis inhibitor VX765 inhibited neuronal apoptosis and improved neurological recovery in mice. These findings indicate that C/EBPβ functions as a key regulator that participates in the microglia pyroptosis-mediated neuroinflammation by activating Fcgr1 transcription.

Keywords:  C/EBPβ; Microglia; Neuroinflammation; Pyroptosis; Spinal cord injury

DOI:  https://doi.org/10.1186/s12974-025-03362-1
J Neuroinflammation. 2025 Jan 31. 22(1): 26

Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.

Kelley C Larson, Frederick W Gergits, Abigail J Renoux, Elizabeth J Weisman, Borislav Dejanovic, Liyue Huang, Bhaumik Pandya, Donald G McLaren, Berkley A Lynch, Richard Fisher, Evan Thackaberry, David Gray, Francois Gaudreault, Christian Mirescu.

Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.

DOI: https://doi.org/10.1186/s12974-025-03346-1
J Neuroinflammation. 2025 Jan 31. 22(1): 27

Exploratory analysis of a Novel RACK1 mutation and its potential role in epileptic seizures via Microglia activation.

Sai Zhang, Zhaofei Dong, Jing Guo, Ze Li, Hong Wu, Linming Zhang, Fuli Min, Tao Zeng.

  Seizures is a prevalent neurological disorder with a largely elusive pathogenesis. In this study, we identified the key gene RACK1 and its novel mutation RACK1-p.L206P as being associated with seizures through single-cell transcriptome sequencing (scRNA-seq) and whole exome sequencing (WES) techniques. Our findings reveal that the RACK1-p.L206P mutation significantly enhances proliferation, migration, phagocytic ability, and inflammatory activation in human microglia, which in turn affects neuronal excitability and synaptic function, culminating in typical seizure symptoms in the seizures. These effects were further validated in a mouse model using CRISPR/Cas9 gene editing technology. Mutant microglia exhibited increased activation and induced apoptosis in hippocampal neurons, leading to higher action potential frequency and excitatory synaptic marker expression. In vivo experiments demonstrated that RACK1-p.L206P mutant mice displayed classic seizure symptoms, with increased neuronal excitability and a tendency for action potential bursts during initial depolarization, along with more frequent spike discharges. Additionally, excitatory synapse density and size in the hippocampal CA1 region of mutant mice were significantly elevated, accompanied by increased expression of VGLUT1 and PSD95 within microglia. This study offers novel insights into the molecular mechanisms underlying seizures in the seizures and presents valuable clues for the development of future therapeutic strategies.

Keywords:  CRISPR/Cas9; Microglia; Neuron; RACK1; Seizures; Whole exome sequencing

DOI:  https://doi.org/10.1186/s12974-025-03350-5
Cancer Cell. 2025 Feb 04. pii: S1535-6108(25)00026-1. [Epub ahead of print]

Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases.

Francisco Javier Rodriguez-Baena, Angel Marquez-Galera, Pablo Ballesteros-Martinez, Alba Castillo, Eva Diaz, Gema Moreno-Bueno, Jose P Lopez-Atalaya, Berta Sanchez-Laorden.

  Melanoma is one of the tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the role of the brain immune microenvironment in treatment responses are not yet fully understood. Using preclinical models and single-cell transcriptomics, we have identified a mechanism that enhances antitumor immunity in melanoma brain metastasis. We show that activation of the Rela/Nuclear Factor κB (NF-κB) pathway in microglia promotes melanoma brain metastasis. Targeting this pathway elicits microglia reprogramming toward a proinflammatory phenotype, which enhances antitumor immunity and reduces brain metastatic burden. Furthermore, we found that proinflammatory microglial markers in melanoma brain metastasis are associated with improved responses to immune checkpoint inhibitors in patients and targeting Rela/NF-κB pathway in mice improves responses to these therapies in the brain, suggesting a strategy to enhance antitumor immunity and responses to immune checkpoint inhibitors in patients with melanoma brain metastasis.

Keywords:  Rela/NF-kB; immune checkpoint inhibitors; melanoma brain metastasis; microglia

DOI:  https://doi.org/10.1016/j.ccell.2025.01.008
Int Immunopharmacol. 2025 Feb 03. pii: S1567-5769(25)00182-1. [Epub ahead of print]149 114192

Inhibiting HMGB1/AGER/NF-κB pathway prevents pro-inflammatory microglia polarization and protect photoreceptors in retinitis pigmentosa.

Chengyu Hu, Tao Cui, Zihang Xu, Kun Yang, Yan Wu, Wenting Cai, Jing Yu, Yaoyan Qiu.

   PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal neurodegenerative disease which is a significant contributor to blindness. Microglia-mediated inflammation plays a crucial role in retinitis pigmentosa. However, the activation mechanisms of microglia and the role of polarized microglia in RP remain unclear. High-mobility group box 1 (HMGB1) is a key contributor to aseptic inflammation, and glycyrrhizin exerts anti-inflammatory effects by targeting HMGB1. This study aimed to investigate the role of HMGB1 and microglia in RP and explore the protective effects of glycyrrhizin on photoreceptors.
METHODS: Male C57BL/6 mice and age-matched rd1 mice were used for in vivo models, while zaprinast-treated 661w cells and HMGB1-treated BV-2 cells were used for in vitro models. In this study, the expression of HMGB1 was analyzed using QPCR and western blot (WB). Immunofluorescence staining and ELISA were performed to assess HMGB1 translocation and secretion. Glycyrrhizin was used to inhibit HMGB1, while FPS-ZM1 served as an inhibitor of the receptor for advanced glycation end products (AGER). Microglial polarization was evaluated by QPCR, and the HMGB1/ AGER/ NF-κB signaling pathway was analyzed through WB. Photoreceptor degeneration and visual function were assessed through H&E staining, electroretinography, and TUNEL staining.
RESULTS: We observed elevated levels of HMGB1 in the retina of rd1 mice and demonstrated in vitro that photoreceptors may serve as a significant source of HMGB1 in the retina. Additionally, HMGB1 was observed to cause microglial polarization via the HMGB1/AGER/ NF-κB pathway and the polarized microglia secrete inflammatory factors including TNF-α and IL-1β which accelerates the degeneration of photoreceptors. Glycyrrhizin reversed the degeneration of photoreceptors and loss of visual function in rd1 mice through the HMGB1/AGER/ NF-κB pathway.
CONCLUSION: Our findings showed that HMGB1 secreted by photoreceptors activated the microglia through the HMGB1/AGER/NF-κB pathway and the polarized microglia accelerates the degeneration of photoreceptors. Glycyrrhizin reversed the polarization caused by HMGB1 in vitro and delayed the progression of RP in vivo, presenting a potential novel approach for treating retinitis pigmentosa.

Keywords:  Animal study; Glycyrrhizin; HMGB1; Microglia; Retinitis pigmentosa

DOI:  https://doi.org/10.1016/j.intimp.2025.114192
Int Immunopharmacol. 2025 Jan 30. pii: S1567-5769(25)00106-7. [Epub ahead of print]148 114117

Dapagliflozin alleviated seizures and cognition impairment in pilocarpine induced status epilepticus via suppressing microglia-mediated neuroinflammation and oxidative stress.

Ying Liu, Yuhang Yu, Changling Chen, Xuling Wu, Qian Zheng, Xiangming Zhang, Lan Ye, Chunlin Zhang, Zhanhui Feng.

   BACKGROUND: Status epilepticus (SE) is a neurological emergency with prolonged seizures leading to chronic epilepsy, cognitive impairment, and neuronal damage. Microglial activation, subsequent neuroinflammation and oxidative stress contribute to SE-induced neuronal injury. Single-cell sequencing has delineated the pro-inflammatory microenvironment in epileptic lesions, characterized by widespread microglial activation. Dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), has shown potential in modulating neuroinflammatory responses. This study aimed to investigate the effects of Dapagliflozin on seizure and cognitive impairment by alleviating microglia-mediated neuroinflammation, oxidative stress.
METHODS: Single-Cell Transcriptomic Analysis were used to reveal SLC5A2 cellular heterogeneity and subtype-specific signatures of Temporal lobe Epilepsy. Male C57BL/6 mice were administered pilocarpine. Dapagliflozin were injected immediately after the termination of SE and at 24-hour intervals after SE until sacrifice. The latency and seizure score were recorded. Morris water maze were used to evaluate cognitive function of mouse. The neuroinflammation cell model was induced by lipopolysaccharide(LPS) in BV2 cell. Immunofluorescent staining, immunohistochemistry, flow cytometry, western blot, RT-qPCR, ELISA etc were used to examine the activation of microglia, evaluate neuroinflammation and oxidative stress.
RESULTS: The expression of SLC5A2 is up-regulated in microglia of epileptic patients. Administration of Dapagliflozin significantly reduced seizure activity and improved cognitive performance in SE mouse. Dapagliflozin reduced microglial activation, as indicated by downregulation of CD86, iNOS expression and increased CD206, Arg-1 level. Dapagliflozin decreased oxidative stress, as evidenced by reduced levels of malondialdehyde (MDA), reactive oxygen species (ROS), increased superoxide dismutase (SOD) and Glutathione (GSH) activity. In addition, Dapagliflozin treatment can rescured the neuronal damage and suppressed the release of inflammatory cytokines such as IL-6, IL-18 and IL-1β.
CONCLUSION: Our findings suggest that Dapagliflozin exerts neuroprotective effects by modulating microglia-mediated neuroinflammation and oxidative stress. The inhibition of SGLT2 may represent a novel therapeutic strategy for the treatment of SE and associated cognitive impairments.

Keywords:  Cognitive impairment; Dapagliflozin; Microglia; Neuroinflammation; Oxidative stress; SGLT2 inhibition; Status epilepticus

DOI:  https://doi.org/10.1016/j.intimp.2025.114117
Immunity. 2025 Jan 31. pii: S1074-7613(25)00032-9. [Epub ahead of print]

NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.

Róisín M McManus, Max P Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C M Schlachetzki, David S Bouvier, Michelle-Amirah Khalil, Mario A Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F Rodríguez-Alcázar, Susanne V Schmidt, Jasper Spitzer, Peri Noori, Alberto Maillo, Andreas Boettcher, Brian Herron, John McConville, David Gomez-Cabrero, Jesper Tegnér, Christopher K Glass, Karsten Hiller, Eicke Latz, Michael T Heneka.

  Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition in vivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.

Keywords:  Alzheimer’s disease; NLRP3; amyloid-β; dementia; glutamine metabolism; inflammasome; microglia; phagocytosis; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.immuni.2025.01.007
Antioxid Redox Signal. 2025 Feb 03.

GPx3 Promotes Functional Recovery after Spinal Cord Injury by Inhibiting Microglial Pyroptosis Through IRAK4/ROS/NLRP3 Axis.

Zhongyuan Liu, Jiawei Shi, Kewu Tu, Hao Ma, Jiayu Chen, Xin Xiang, Peiqian Zou, Congrui Liao, Ruoting Ding, Zucheng Huang, Xinqiang Yao, Jianting Chen, Liang Wang, Zhongmin Zhang.

  Aim: Spinal cord injury (SCI) is a catastrophic injury characterized by oxidative stress. Glutathione peroxidase 3 (GPx3) is an antioxidant enzyme that protects against immune responses in various diseases. However, the effects of GPx3 in SCI remains unclear. This study aimed to investigate the role of GPx3 in SCI and its underlying mechanisms. Results: We injected adeno-associated viruses to overexpress GPx3 in mice. Primary microglia and BV2 cells were used as in vitro models. We knocked down or overexpressed GPx3 in BV2 cells. Additionally, BV2 cells transfected with siIRAK4 were used to perform rescue experiments. A series of histological and molecular biological analyses were used to explore the role of GPx3 in SCI. Overexpression of GPx3 inhibited oxidative stress in mice, improving functional recovery after SCI. Similarly, LPS+ATP stimulation decreased GPx3 expression in microglia. Silencing of GPx3 elevated the generation of reactive oxygen species, increased the expression of IRAK4 and pro-inflammatory factors, and promoted pyroptosis in microglia. However, overexpression of GPx3 reversed these results. Moreover, silencing of IRAK4 alleviated these phenomena, which were upregulated by GPx3 deficiency. Innovation and Conclusion: Our results demonstrated that GPx3 plays a critical role in SCI by inhibiting microglial pyroptosis via the IRAK4/ROS/NLRP3 signaling pathway. Antioxid. Redox Signal. 00, 000-000.

Keywords:  Glutathione peroxidase 3; microglia; neuroinflammation; pyroptosis; spinal cord injury

DOI:  https://doi.org/10.1089/ars.2024.0618
J Theor Biol. 2025 Jan 30. pii: S0022-5193(25)00015-3. [Epub ahead of print]602-603 112049

A mathematical model of microglia glucose metabolism and lactylation with positive feedback.

Kamila Larripa, Anca Rǎdulescu.

  In this paper, we present and analyze a model for metabolism and lactylation in a single microglia. The model includes positive feedback from lactylation in the glycolytic pathway, and links metabolism and inflammation. Specific pathways include the transition of glucose to pyruvate to lactate in a microglia, as well as the gradient transport of glucose and lactate into and out of the cell. Additionally, the upregulation of certain pathways by either epigenetic modification or the inflammatory response are included. Bifurcation and sensitivity analyses demonstrate the importance of key parameters and pathways in the model, specifically the role of lactylation. Our model is validated by qualitatively reproducing recent in vitro experiments in which exogenous glucose and lactate are modified.

Keywords:  Bifurcation analysis; Differential equations; Feedback; Metabolism; Microglia

DOI:  https://doi.org/10.1016/j.jtbi.2025.112049
J Vis Exp. 2025 Jan 17.

Derivation of a Human Brain Organoid with Microglia Development.

Tongguang Wang, Benjamin D Gastfriend, Valerie McDonald, Joseph P Steiner, Abdel G Elkahloun, Avindra Nath.

Three-dimensional (3D) brain organoid cultures derived from induced pluripotent stem cells (iPSC) provide an important alternative in vitro tool for studying human brain development and pathogenesis of neurological diseases. However, the lack of incorporation of microglia in the human brain organoids is still a major hurdle for 3D models of neuroinflammation. Current approaches include either the incorporation of fully differentiated microglia into mature brain organoids or the induction of microglial differentiation from the early stage of iPSC-derived embryoid bodies (EBs). The first approach misses the stage when microglial differentiation interacts with the adjacent neural environment, and the later approach is technically challenging, resulting in inconsistency among the final organoids in terms of the quantity and quality of microglia. To model brain organoids with microglia to study the early interactions between microglial and neuronal development, highly pure hematopoietic progenitor cells (HPC) differentiated from human iPSCs were incorporated into iPSC-derived EBs to make brain organoids. Using immunostaining and single-cell RNA sequencing (sc-RNA-seq) analysis, we confirmed that HPCs were incorporated into the 3D organoids, which eventually developed into brain organoids with both microglia and neurons. Compared to brain organoids without HPCs, this approach produces significant microglial incorporation in the brain organoids. This novel 3D organoid model, which consists of both microglial and neural development properties, can be used to study the early interactions between innate immune and nervous system development and potentially as a model for neuroinflammation and neuroinfectious disorders.

DOI: https://doi.org/10.3791/67491
J Neuroinflammation. 2025 Feb 07. 22(1): 33

Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology.

Robin Christ, Devon Siemes, Shuo Zhao, Lars Widera, Philippa Spangenberg, Julia Lill, Stephanie Thiebes, Jenny Bottek, Lars Borgards, Andreia G Pinho, Nuno A Silva, Susana Monteiro, Selina K Jorch, Matthias Gunzer, Bente Siebels, Hannah Voss, Hartmut Schlüter, Olga Shevchuk, Jianxu Chen, Daniel R Engel.

Infection with enterohemorrhagic E. coli (EHEC) causes severe changes in the brain leading to angiopathy, encephalopathy and microglial activation. In this study, we investigated the role of tumour necrosis factor alpha (TNF-α) for microglial activation and brain pathology using a preclinical mouse model of EHEC infection. LC-MS/MS proteomics of mice injected with a combination of Shiga toxin (Stx) and lipopolysaccharide (LPS) revealed extensive alterations of the brain proteome, in particular enrichment of pathways involved in complement activation and coagulation cascades. Inhibition of TNF-α by the drug Etanercept strongly mitigated these changes, particularly within the complement pathway, suggesting TNF-α-dependent vasodilation and endothelial injury. Analysis of microglial populations using a novel human-in-the-loop deep learning algorithm for the segmentation of microscopic imaging data indicated specific morphological changes, which were reduced to healthy condition after inhibition of TNF-α. Moreover, the Stx/LPS-mediated angiopathy was significantly attenuated by inhibition of TNF-α. Overall, our findings elucidate the critical role of TNF-α in EHEC-induced brain pathology and highlight a potential therapeutic target for mitigating neuroinflammation, microglial activation and injury associated with EHEC infection.

DOI: https://doi.org/10.1186/s12974-025-03356-z
Front Pharmacol. 2025 ;16 1462699

A ketogenic diet regulates microglial activation to treat drug addiction.

Jie Ji, Yi Tang.

  Drug addiction is a chronic and potentially deadly disease that is considered a global health problem and describes the alteration of brain function by psychostimulant drugs through changes in the reward system. However, there is still no ideal strategy for the management of drug addiction. Previous studies have suggested that microglia are involved in events associated with neuroplasticity and memory, which are also related to drug addiction. Many studies have shown that psychoactive substances may act directly on immune cells, altering their function and inducing the production of various inflammatory mediators. In recent years, a ketogenic diet (KD) was shown to have therapeutic benefits as a dietary therapy for a variety of neurological disorders. With respect to drug addiction, studies have shown that a KD can alleviate glucose metabolism disorders caused by alcohol use disorders by increasing ketone metabolism, thereby reducing withdrawal symptoms. This finding indicates the potential of a KD as a treatment for drug addiction, since a KD may promote the transition of microglia to a predominantly anti-inflammatory state through several mechanisms. Here, we discuss recent research showing that a KD plays a variety of roles in controlling microglia-mediated inflammation, opening new treatment avenues to treat drug addiction. This succinct analysis offers evidence of the enormous potential of a KD to treat drug addiction through the inhibition of microglial activation.

Keywords:  drug addiction; inflammation; ketogenic diet; microglia; βhydroxybutyrate

DOI:  https://doi.org/10.3389/fphar.2025.1462699
J Neuroinflammation. 2025 Feb 05. 22(1): 32

CD22 modulation alleviates amyloid β-induced neuroinflammation.

Yu Dong Mai, Qingqing Zhang, Cheuk Lim Fung, Shui On Leung, Chi Ho Chong.

  Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.

Keywords:  Alzheimer’s disease; Amyloid β; CD22; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03361-2
Invest Ophthalmol Vis Sci. 2025 Feb 03. 66(2): 2

Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.

Guannan Wu, Shoji Notomi, Ziming Xu, Yosuke Fukuda, Yusuke Maehara, Yan Tao, Huanyu Zhao, Keijiro Ishikawa, Yusuke Murakami, Toshio Hisatomi, Koh-Hei Sonoda.

Purpose: Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a lysosomal protein essential for autophagosome maturation and lysosome biogenesis, in maintaining retinal health under oxidative stress.
Methods: To induce oxidative stress, young Lamp2 knockout (KO) and wild-type mice received an intravenous injection of a low dose (10 mg/kg) of sodium iodate (NaIO3). We examined retinal histopathology and morphological changes in the RPE. The involvement of resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, and real-time PCR for chemokines and cytokines.
Results: After administering a low-dose NaIO3, Lamp2 KO mice showed significant RPE degeneration, whereas wild-type mice had minimal damage. Histological analysis and electron microscopy revealed significant thinning of the outer nuclear layer and loss of RPE epithelial polarity in Lamp2 KO mice. Additionally, there was a significant increase in ionized calcium-binding adaptor molecule 1-positive microglia and macrophages in the outer retina. Early proliferation of CD45lowMHC-IIlow resident microglia was followed by the infiltration of CD45highLy6Chigh monocytes and the engraftment of CD11b+CD45high monocyte-derived macrophages. Transcript levels of monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, Il- 1β, and Il-6 also increased in the retinas of Lamp2 KO mice. Furthermore, pretreatment with the macrophage-depleting agent clodronate prevented NaIO3-induced RPE degeneration and macrophage infiltration in Lamp2 KO mice.
Conclusions: Lamp2 deficiency, when combined with oxidative stress, leads to RPE degeneration in vivo. Lysosomal dysfunction also promotes macrophage engraftment and triggers neurotoxic inflammation.

DOI: https://doi.org/10.1167/iovs.66.2.2
Sci Rep. 2025 Jan 31. 15(1): 3932

CNS resident macrophages exhibit region-specific states and immunogenic responses during Rbpj-deficient brain arteriovenous malformation.

Sera Nakisli, Kayleigh Fanelli, Julia LaComb, Lily J Arnold, Corinne M Nielsen.

  Microglia are heterogeneous macrophage cells that serve as the central nervous system's resident immune cells. During neuro-related diseases, CNS resident macrophages change their molecular, cellular, and functional properties-that collectively define "states"-in response to specific neural perturbations. Neurovascular diseases elicit state changes, by promoting increased vascular permeability among microvessels and thus altering blood-brain barrier integrity. Here, we used a mouse model of brain arteriovenous malformation (bAVM)-mediated by endothelial loss of Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)-to investigate changes to brain resident macrophage states during neurovascular disease pathogenesis. We found increased area of Ionized calcium-binding adapter molecule 1 (Iba1) expression in Rbpj-deficient bAVM tissue, as well as Iba1 + cell hypertrophy, increased cell number, and hyperproliferation within areas of increased Iba1 + density. Hypertrophic cells had increased cell body areas and decreased process length, suggesting a transition in surveillance state. Gene expression data revealed region-specific molecular changes to Iba + cells, suggestive of altered metabolic activity. CNS resident macrophages isolated from cortical and cerebellar regions showed profiles consistent with cytokine-associated immunogenic responses and an immunovigilant pathogen-recognition response, respectively. Thus, our findings demonstrate region-specific changes to CNS resident macrophages during Rbpj-deficient bAVM.

Keywords:  Brain; Microglia; Mouse; Rbpj; Vascular malformation; Vessel permeability

DOI:  https://doi.org/10.1038/s41598-025-86150-4
Biol Psychiatry. 2025 Jan 30. pii: S0006-3223(25)00064-2. [Epub ahead of print]

Interneuron loss and microglia activation by transcriptome analyses in the basal ganglia of Tourette disorder.

Yifan Wang, Liana Fasching, Feinan Wu, Milovan Suvakov, Anita Huttner, Sabina Berretta, Rosalinda Roberts, James F Leckman, Thomas V Fernandez, Alexej Abyzov, Flora M Vaccarino.

   BACKGROUND: Tourette disorder is characterized by motor hyperactivity and tics that are believed to originate in basal ganglia. Postmortem immunocytochemical analyses previously revealed decreases in cholinergic, parvalbumin, and somatostatin interneurons (IN) within the caudate/putamen of individuals with TS.
METHODS: We obtained transcriptome and open chromatin datasets by snRNAseq and snATAC-seq, respectively, from caudate/putamen postmortem specimens of 6 adult TS and 6 matched normal control (NC). Differential gene expression and differential chromatin accessibility analyses were performed in identified cell types.
RESULTS: The data reproduced the known cellular composition of the human striatum, including a majority of medium spiny neurons (MSN) and small populations of GABAergic and cholinergic IN. IN were decreased by ∼50% in TS brains, with no difference in other cell types. Differential gene expression analysis suggested that mitochondrial oxidative metabolism in MSN and synaptic adhesion and function in IN were both decreased in TS subjects, while there was activation of immune response in microglia. Gene expression changes correlated with changes in activity of cis-regulatory elements, suggesting a relationship of transcriptomic and regulatory abnormalities in MSN, OL and AST of TS brains.
CONCLUSIONS: This initial analysis of the TS basal ganglia transcriptome at the single cell level confirms the loss and synaptic dysfunction of basal ganglia IN, consistent with in vivo basal ganglia hyperactivity. In parallel, oxidative metabolism was decreased in MSN and correlated with activation of microglia cells, attributable at least in part to dysregulated activity of putative enhancers, implicating altered epigenomic regulation in TS.

Keywords:  Tourette disorder; human; interneurons; microglia; multi-omics; striatum

DOI:  https://doi.org/10.1016/j.biopsych.2024.12.022
IBRO Neurosci Rep. 2025 Jun;18 211-221

Allopregnanolone relieves paclitaxel induced mechanical hypersensitivity via inhibiting spinal cord PGE2-EP2 mediated microglia-neuron signaling.

Kunlin Guo, Lei Gao, Ping Li, Shanwu Feng, Liping Zhao, Xian Wang.

  Chemotherapy-induced neuropathic pain (CINP) is a serious adverse effect of commonly used chemotherapeutics. Neurosteroid allopregnanolone is suggested to modulate the expression of various receptors or enzymes that involved in pain perception, presenting an analgesic potential. Here, we investigated if allopregnanolone attenuates extracellular signal-regulated kinase (ERK) and its downstream prostaglandin E2 (PGE2) expression in the dorsal spinal cord concomitant with neuropathic pain relief in paclitaxel (PTX)-induced neuropathic pain model rats. The results showed PTX upregulated phosphorylated ERK (p-ERK), PGE2 level, and PGE2 receptor E-prostanoid 2 (EP2) expression in the spinal dorsal horn. Besides, p-ERK inhibitor PD98059 or microglia inhibitor minocycline reduced microglial activation, p-ERK expression, PGE2 release, EP2 expression, and partially alleviated PTX-induced mechanical hypersensitivity. Further, allopregnanolone level in the dorsal spinal cord was observed to decrease in CINP rats, and intragastric administration of exogenous allopregnanolone dose-dependently alleviated PTX-induced mechanical hypersensitivity. Mechanistically, allopregnanolone dose-dependently alleviated PTX-induced microglial activation, p-ERK, PGE2, and EP2 upregulation, as well as cytokines expression in the dorsal spinal cord in CINP rats. Furthermore, subcutaneous injection of allopregnanolone synthesis inhibitor medroxyprogesterone could reduce endogenous allopregnanolone and block all effects of exogenous allopregnanolone in CINP rats. Taken together, these results suggest allopregnanolone presents an analgesic effect for PTX-induced mechanical hypersensitivity, partially via inhibiting the dorsal spinal cord PGE2-EP2 mediated microglia-neuron signaling.

Keywords:  Allopregnanolone; Chemotherapy-induced neuropathic pain; Microglial; PGE2; Paclitaxel; Spinal cord

DOI:  https://doi.org/10.1016/j.ibneur.2025.01.011