bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–03–16
fifteen papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Novel mRNA isoforms in human microglia refine genetic associations with neurodegeneration.
  2. Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration.
  3. Single-cell analysis identifies MKI67+ microglia as drivers of neovascularization in proliferative diabetic retinopathy.
  4. The role of myeloid cell heterogeneity during spontaneous choroidal neovascularization in Vldlr knockout mice.
  5. Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.
  6. Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.
  7. Exploring a patient-specific in vitro pipeline for stratification and drug response prediction of microglia-based therapeutics.
  8. Microglia mediate the early-life programming of adult glucose control.
  9. SP3-Mediated Transcriptional Activation of GRIK1 is Involved in Alzheimer's Disease-Induced Cognitive Decline by Inducing Inflammasome Activation in Microglia.
  10. Intravitreal delivery of NMO-IgG causes primary retinal damage in the absence of optic nerve injury.
  11. A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases.
  12. Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.
  13. Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.
  14. Centripetal migration and prolonged retention of microglia promotes spinal cord injury repair.
  15. Galectin-3 activates microglia and promotes neurological impairment via NLRP3/pyroptosis pathway following traumatic brain injury.
  1. Nat Genet. 2025 Mar;57(3): 492-493
    Novel mRNA isoforms in human microglia refine genetic associations with neurodegeneration.
      
    DOI:  https://doi.org/10.1038/s41588-025-02112-6
  2. Neuron. 2025 Mar 05. pii: S0896-6273(25)00120-5. [Epub ahead of print]
    Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration.
    Rocio Vicario, Stamatina Fragkogianni, Maria Pokrovskii, Carina Meyer, Estibaliz Lopez-Rodrigo, Yang Hu, Masato Ogishi, Araitz Alberdi, Ann Baako, Oyku Ay, Isabelle Plu, Véronique Sazdovitch, Sebastien Heritier, Fleur Cohen-Aubart, Natalia Shor, Makoto Miyara, Florence Nguyen-Khac, Agnes Viale, Ahmed Idbaih, Zahir Amoura, Marc K Rosenblum, Haochen Zhang, Elias-Ramzey Karnoub, Palash Sashittal, Akhil Jakatdar, Christine A Iacobuzio-Donahue, Omar Abdel-Wahab, Viviane Tabar, Nicholas D Socci, Olivier Elemento, Eli L Diamond, Bertrand Boisson, Jean-Laurent Casanova, Danielle Seilhean, Julien Haroche, Jean Donadieu, Frederic Geissmann.
      Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.
    Keywords:  MAPK pathway; Neurodegeneration; brainstem; hippocampus; microglia; resident macrophages
    DOI:  https://doi.org/10.1016/j.neuron.2025.02.007
  3. J Transl Med. 2025 Mar 11. 23(1): 310
    Single-cell analysis identifies MKI67+ microglia as drivers of neovascularization in proliferative diabetic retinopathy.
    Keyi Zou, Xue Li, Bibo Ren, Fu Cheng, Jian Ye, Zelin Ou.
       BACKGROUND: Proliferative diabetic retinopathy (PDR) is among the primary causes of blindness in individuals with diabetes. Elevated lactate levels have been identified as a critical biomarker associated with the prognosis of PDR. While significant lactate accumulation has been observed in the vitreous fluid of PDR patients, the detailed pathways through which lactate impacts pathological neovascularization remain insufficiently elucidated.
    METHODS: The study employed single-cell RNA sequencing (scRNA-seq) to identify and characterize lactate-associated cell type in PDR patients. Key gene expression profiles and molecular pathways associated with lactate metabolism were analyzed. In vitro experiments were conducted using microglial cell cultures treated with high-glucose conditions (50 mM) to assess the induction of lactate metabolism-related genes. Additionally, an oxygen-induced retinopathy (OIR) mouse model was used to evaluate the impact of abemaciclib, an FDA-approved proliferation inhibitor, on retinal neovascularization.
    RESULTS: To the best of our knowledge, this investigation is the first to delineate a novel microglial subset, designated as MKI67+ microglia, distinguished by robust upregulation of genes implicated in lactate metabolic processes and proliferation, such as MKI67, PARK7 and LDHA, as well as a pronounced enrichment of glycolysis-associated molecular pathways. This unique cell type promotes angiogenesis by interacting with endothelial cells via secreted phosphoprotein 1 (SPP1)-Integrin alpha 4 (ITGA4) signaling. In vitro experiments have shown the use of 50 mM high glucose to simulate microglia in PDR environment and observe its promotion of vascular proliferation. In the in vivo OIR model, treatment with abemaciclib, a FDA-approved proliferation inhibitor, significantly reduced neovascularization.
    CONCLUSION: The identification of MKI67+ microglia as a cell type strongly associated with lactate metabolism provides a novel perspective on the mechanisms underlying PDR onset. These findings expand our understanding of the cellular and metabolic dynamics in PDR, emphasizing potential implications for targeted therapeutic interventions.
    Keywords:  Abemaciclib; Lactate metabolic gene; Microglia; Oxygen-induced retinopathy; Proliferative diabetic retinopathy; Single cell analysis
    DOI:  https://doi.org/10.1186/s12967-025-06320-w
  4. J Neuroinflammation. 2025 Mar 07. 22(1): 70
    The role of myeloid cell heterogeneity during spontaneous choroidal neovascularization in Vldlr knockout mice.
    Amrita Rajesh, Joyce Gong, Kyle S Chan, Ritvik Viniak, Steven Droho, David Kachar, Joshua Y Strauss, Andrew L Wang, Jeremy A Lavine.
       BACKGROUND: Myeloid cells are heterogeneous cells that are critical for spontaneous choroidal neovascularization (CNV) in the Vldlr-/- mouse model. However, the specific myeloid cell subtype necessary for CNV remains unknown.
    METHODS AND RESULTS: To investigate the role of monocytes, we bred Ccr2-/- and Nr4a1-/- mice into the Vldlr-/- background. We found that Ccr2 and Nr4a1 deficiency had no effect upon macrophage counts, CNV lesion number, or total CNV area. Next, we investigated the role of microglia by generating Vldlr-/-Tmem119CreER/+Rosa26DTR/+ mice. Diphtheria toxin (DT) treatment reduced macrophage counts at CNV lesions and CNV lesion number, but did not affect total CNV lesion area. To target microglia via a second strategy, we generated Vldlr-/-Cx3cr1CreERCsf1riDTR mice and treated them with a single low dose of tamoxifen to target microglia without affecting choroidal macrophages. DT treatment in Vldlr-/-Cx3cr1CreERCsf1riDTR mice decreased macrophage counts at CNV lesions and CNV lesion number but again had no effect upon total CNV lesion area. To target choroidal macrophages and microglia, we treated Vldlr-/-Cx3cr1CreERCsf1riDTR mice with 9 tamoxifen treatments. DT-treated mice showed dramatic reductions in macrophage counts, CNV number, and total lesion area.
    CONCLUSIONS: These data suggest that monocytes and monocyte-derived macrophages are dispensable, microglia are likely initiators for CNV development, and choroidal macrophages are potential key contributors to CNV growth and/or maintenance in the Vldlr-/- model.
    Keywords:  Angiogenesis; Choroidal neovascularization; Macrophage; Macular degeneration; Microglia; Vldlr
    DOI:  https://doi.org/10.1186/s12974-025-03398-3
  5. Nat Commun. 2025 Mar 07. 16(1): 2283
    Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.
    Phillip S Gross, Violeta Durán-Laforet, Lana T Ho, George S Melchor, Sameera Zia, Zeeba Manavi, William E Barclay, Sung Hyun Lee, Nataliia Shults, Sean Selva, Enrique Alvarez, Jason R Plemel, Meng-Meng Fu, Dorothy P Schafer, Jeffrey K Huang.
      The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
    DOI:  https://doi.org/10.1038/s41467-025-57632-w
  6. Cell Rep. 2025 Mar 07. pii: S2211-1247(25)00153-6. [Epub ahead of print]44(3): 115382
    Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.
    Olga I Kahn, Sara L Dominguez, Caspar Glock, Margaret Hayne, Steve Vito, Arundhati Sengupta Ghosh, Max Adrian, Braydon L Burgess, William J Meilandt, Brad A Friedman, Casper C Hoogenraad.
      Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.
    Keywords:  ALS; CP: Neuroscience; NfL; biomarkers; calpain proteolysis; microglial activation; myeloid cell activation; neurodegeneration; neuroinflammation; neuronal injury; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2025.115382
  7. Sci Rep. 2025 Mar 10. 15(1): 8296
    Exploring a patient-specific in vitro pipeline for stratification and drug response prediction of microglia-based therapeutics.
    Carla Cuní-López, Romal Stewart, Satomi Okano, Garry L Redlich, Mark W Appleby, Anthony R White, Hazel Quek.
      The scarcity of effective biomarkers and therapeutic strategies for predicting disease onset and progression in neurodegenerative diseases such as Alzheimer's disease (AD) is a major challenge. Conventional drug discovery approaches have been unsuccessful in providing efficient interventions due to their 'one-size-fits-all' nature. As an alternative, personalised drug development holds promise to pre-select responders and identifying suitable indicators of drug efficacy. In this exploratory study, we have established a pipeline with the potential to guide patient stratification studies before clinical trials. This pipeline uses 2D and 3D in vitro models of monocyte-derived microglia-like cells (MDMi) from AD and mild cognitive impairment (MCI) patients, and matched healthy control (HC) individuals. By profiling cytokine responses in these models using multidimensional analyses, we have observed that the 3D model offers a more defined separation of profiles between individuals based on disease status. While this pilot study focuses on AD and MCI, future investigations incorporating other neurodegenerative disorders will be necessary to validate the pipeline's findings and demonstrate its broader applicability.
    Keywords:  2D and 3D in vitro models; MDMi; Monocyte-derived microglia; Patient stratification; Preclinical drug testing; Preclinical pipeline for prediction
    DOI:  https://doi.org/10.1038/s41598-025-92593-6
  8. Cell Rep. 2025 Mar 12. pii: S2211-1247(25)00180-9. [Epub ahead of print]44(3): 115409
    Microglia mediate the early-life programming of adult glucose control.
    Martin Valdearcos, Emily R McGrath, Stephen M Brown Mayfield, Melissa G Jacuinde, Andrew Folick, Rachel T Cheang, Ruoyu Li, Tomas P Bachor, Rachel N Lippert, Allison W Xu, Suneil K Koliwad.
      Glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for synapse formation between hypothalamic glucoregulatory centers. Although microglia prune synapses throughout the brain, their role in refining hypothalamic glucoregulatory circuits remains unclear. Here, we show that the phagocytic activity of microglia in the mediobasal hypothalamus (MBH) is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In addition to actively engulfing synapses, microglia are critical for refining perineuronal nets (PNNs) within the neonatal MBH. Remarkably, transiently depleting microglia before weaning (postnatal day [P]6-16) but not afterward (P21-31) induces glucose intolerance in adulthood due to impaired insulin responsiveness, which we link to PNN overabundance and reduced synaptic connectivity between hypothalamic glucoregulatory neurons and the pancreatic β cell compartment. Thus, microglia facilitate early-life synaptic plasticity in the MBH, including PNN refinement, to program hypothalamic circuits regulating adult glucose homeostasis.
    Keywords:  CP: Metabolism; CP: Neuroscience; glucose homeostasis; hypothalamus; insulin; metabolic programming; microglia; neonatal; perineuronal nets; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.celrep.2025.115409
  9. Neuromolecular Med. 2025 Mar 07. 27(1): 22
    SP3-Mediated Transcriptional Activation of GRIK1 is Involved in Alzheimer's Disease-Induced Cognitive Decline by Inducing Inflammasome Activation in Microglia.
    Xiaolin Pang, Zhun Wang, Mengxue Zhang, Jinpeng Dong, Zhonglan Dong, Yiqing Yin.
      GRIK1 has been identified to suppress the activation of NLRP3 inflammasome. The present study investigated the damaging effect of GRIK1 on Alzheimer's disease (AD), the most common neurodegenerative disease, by focusing on inflammasome. APP-PS1 mice were subjected to a Y-maze test and a Morris water maze test. APP-PS1 mice with GRIK1 knockdown were constructed using adeno-associated virus, and the effects of GRIK1 knockdown on the NLRP3 inflammasome activation in microglia of brain tissues of APP-PS1 mice were analyzed. Mouse primary microglia BV2 was induced by LPS, and Western blot, flow cytometry, and ELISA were performed. GRIK1 was significantly elevated in the brain tissues of APP-PS1 mice. GRIK1 knockdown inhibited the neuronal damage and NLRP3 neuroinflammation in the brain tissues and improved cognitive dysfunction of APP-PS1 mice. Knockdown of GRIK1 inhibited activation of NLRP3 inflammasome in BV2 cells. SP3 was upregulated in the brain tissues of APP-PS1 mice, and SP3 promoted GRIK1 transcription by binding to its promoter. Overexpression of GRIK1 reversed the mitigating effect of knockdown of SP3 on cognitive dysfunction and NLRP3 activation in APP-PS1 mice. Overall, our results revealed that SP3-induced GRIK1 transcription potentiates NLRP3 inflammasome activation in microglia, leading to cognitive dysfunction in AD.
    Keywords:  Alzheimer’s disease; GRIK1; Microglia; NLRP3 inflammasome; SP3
    DOI:  https://doi.org/10.1007/s12017-025-08844-2
  10. J Neuroinflammation. 2025 Mar 07. 22(1): 69
    Intravitreal delivery of NMO-IgG causes primary retinal damage in the absence of optic nerve injury.
    Biyue Chen, Huanfen Zhou, Mingming Sun, Wanqun Yang, Qianqian Li, Kaishu Yang, Honglu Song, Quangang Xu, Xintong Xu, Yuyu Li, Yanyan Yu, Shihui Wei, Tingjun Chen.
       BACKGROUND: Neuromyelitis Optica (NMO) is a neuroimmune disorder primarily driven by autoantibodies against aquaporin 4 (AQP4), known as NMO-IgG. Although the mechanisms underlying NMO-IgG-induced retinopathy are not fully understood, the high expression of AQP4 in retinal Müller cells suggests a direct interaction that may trigger inflammatory processes in the retina. Previous studies indicate that microglia play a critical role in mediating immune responses, leading to neuronal dysfunction.
    METHODS: NMO-IgG obtained from clinical patients was administered via intravitreal injection to female C57BL/6 mice. Techniques such as optical coherence tomography (OCT), Flash Visual Evoked Potential (f-VEP), electroretinography (ERG), real-time fluorescence quantitative PCR (RT-qPCR), and immunofluorescence analyses were used to assess retinal changes. The potential for reversing retinopathy was explored by depleting microglial cells using the CSF1 receptor inhibitor PLX3397. Additionally, a Transwell co-culture system of MIO-M1 (Müller cells) and BV2 (microglia) cells was established to study their interactions.
    RESULTS: Intravitreal injection of purified NMO-IgG in mouse models led to its deposition in the retina and downregulation of AQP4 in provided. Vascular leakage was observed, alongside retinal dysfunction characterized by thinning of the retinal nerve fiber layer (RNFL) and loss of retinal ganglion cells (RGCs). On day 7, C3 expression was upregulated in Müller cells, followed by microglial activation. Significant morphological changes in microglia were noted, with increased expression of iNOS and C1q, indicating substantial activation. Ablating microglia significantly mitigated NMO-IgG-induced injury to RGCs. In vitro, NMO-IgG-treated MIO-M1 cells secreted higher levels of C3, enhancing the activation and migration of BV2 cells compared to controls.
    CONCLUSIONS: The retinal dysfunction observed in NMO may primarily be linked to the activation of Müller cells by NMO-IgG, leading to increased C3 secretion, which in turn activates microglia. Therapeutic strategies targeting Müller cell-microglia interactions in NMO-IgG-induced retinopathy could be promising in addressing the underlying retinal pathology in this condition.
    Keywords:  C1q; C3; Microglia; Müller cells; NMO; Retinopathy
    DOI:  https://doi.org/10.1186/s12974-025-03380-z
  11. Mol Neurodegener. 2025 Mar 11. 20(1): 29
    A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases.
    Lutgarde Serneels, Annerieke Sierksma, Emanuela Pasciuto, Ivana Geric, Arya Nair, Anna Martinez-Muriana, An Snellinx, Bart De Strooper.
       BACKGROUND: Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia.
    METHODS: We developed the hCSF1Bdes mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additionally, we crossed this model with two humanized App KI mice, the AppHu and the AppSAA. Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimer's disease.
    RESULTS: Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore, we confirmed the multipronged response of microglia in the context of Alzheimer's disease. The hCSF1Bdes and the crosses with the Alzheimer's disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community.
    CONCLUSION: The hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.
    Keywords:  Alzheimer’s disease; Microglia; Mouse xenotransplantation model
    DOI:  https://doi.org/10.1186/s13024-025-00823-2
  12. Sci Transl Med. 2025 Mar 12. 17(789): eadn2635
    Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.
    Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D Kilgore, Di Zhou, Mengxuan Shi, Stephen A Graziose, Jia Fan, Prasad V G Katakam, Aaron S Dumont, Xiaoying Wang.
      Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
    DOI:  https://doi.org/10.1126/scitranslmed.adn2635
  13. J Neuroinflammation. 2025 Mar 07. 22(1): 68
    Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.
    Chae Beom Park, Chan Hee Lee, Gil Myoung Kang, Se Hee Min, Min-Seon Kim.
      Progranulin (PGRN) is a secretory precursor protein composed of 7.5 granulins (GRNs). Mutations in the PGRN-encoding gene Grn have been associated with neurodegenerative diseases. In our previous study, we found that Grn depletion in microglia disrupted glucose metabolism in mice fed a normal chow diet (NCD) but prevented the development of obesity in mice on a high-fat diet (HFD). Given that PGRN regulates lysosomal functions, we investigated lysosomal changes in the hypothalamus of mice with microglia-specific Grn depletion. Here we report that microglia-specific Grn depletion affects the lysosomes of hypothalamic proopiomelanocortin (POMC) neurons and microglia in diet-dependent fashion. Under NCD conditions, microglial Grn depletion led to increased lysosome mass, reduced lysosomal degradative capacity, and accumulation of lipofuscin and cytoplasmic TDP-43 in hypothalamic cells, indicative of lysosomal stress and dysfunction. In contrast, under HFD conditions, the absence of microglial Grn suppressed HFD-induced hypothalamic lysosomal stress. In cultured hypothalamic neurons and microglia, PGRN treatment enhanced lysosomal function, an effect inhibited by PGRN cleavage but restored when its cleavage was blocked. Since HFD feeding promotes the cleavage of hypothalamic PGRN into multi-GRNs and GRNs, the diet-dependent lysosomal changes observed in microglial Grn-depleted mice may be linked to PGRN cleavage. We also demonstrated that intracerebroventricular injection of bafilomycin, which induces lysosomal stress, resulted in microglial activation, inflammation, disrupted POMC neuronal circuitry, and impaired leptin signaling in the hypothalamus-common features of obesity. Our results indicate that microglial PGRN plays an important role in maintaining hypothalamic lysosomal function under healthy diet conditions, whereas increased cleavage of microglial PGRN in states of overnutrition disrupts hypothalamic lysosomal function, thereby fostering hypothalamic inflammation and obesity.
    Keywords:  Granulin; Hypothalamus; Lysosome; Obesity; Progranulin
    DOI:  https://doi.org/10.1186/s12974-025-03370-1
  14. J Neuroinflammation. 2025 Mar 12. 22(1): 77
    Centripetal migration and prolonged retention of microglia promotes spinal cord injury repair.
    Jianan Ye, Fangli Shan, Xinzhong Xu, Chao Liang, Ningyuan Zhang, Hao Hu, Jianjian Li, Fangru Ouyang, Jingwen Wang, Yuanzhe Zhao, Zhida Ma, Congpeng Meng, Ziyu Li, Shuisheng Yu, Juehua Jing, Meige Zheng.
       BACKGROUND: Recent studies have confirmed the critical role of neonatal microglia in wound healing and axonal regeneration following spinal cord injury (SCI). However, the limited migration of microglia to the center of adult lesion may significantly impede their potential benefits.
    METHODS: We established a model of microglial centripetal migration and prolonged retention in C57BL/6J and transgenic mice by injecting exogenous C-X3-C motif chemokine ligand 1 (CX3CL1) and macrophage colony-stimulating factor (M-CSF) directly into the lesion site post-SCI. Wound healing and axonal preservation/regrowth was assessed anatomically, and kinematics analysis was conducted to determine the recovery of locomotor function.
    RESULTS: We identified decreased expression and perilesional distribution of CX3CL1 as the primary reason for the limited centripetal migration of microglia. In situ injection of CX3CL1 into the lesion core promoted microglial centripetal migration, but alone did not improve functional recovery. Nevertheless, a combinational administration of CX3CL1 and M-CSF fostered both centripetal migration and prolonged retention of microglia, thereby effectively displacing blood-derived macrophage infiltration and optimizing wound healing and axonal preservation/regrowth after SCI. Notably, the beneficial effects of CX3CL1 and M-CSF co-administration were specifically blocked in C-X3-C motif chemokine receptor 1 (CX3CR1)-deficient mice. These phenomena may be related to the increase in spleen tyrosine kinase (SYK) levels, which boosts centripetal microglial phagocytosis.
    CONCLUSION: Our study uncovers the criticality of microglial location and abundance in orchestrating SCI repair, highlighting centripetal microglial dynamics as valuable targets for therapeutic intervention.
    Keywords:  CX3CL1; Centripetal migration; M-CSF; Prolonged retention; Spinal cord injury
    DOI:  https://doi.org/10.1186/s12974-025-03411-9
  15. Brain Res. 2025 Mar 10. pii: S0006-8993(25)00118-0. [Epub ahead of print] 149560
    Galectin-3 activates microglia and promotes neurological impairment via NLRP3/pyroptosis pathway following traumatic brain injury.
    Yan Sun, Sheng-Qing Gao, Xue Wang, Tao Li, Yan-Ling Han, Shu-Hao Miao, Ran Zhao, Xiao-Bo Zheng, Jia-Yin Qiu, Wang-Xuan Jin, Chao-Chao Gao, Meng-Liang Zhou.
       BACKGROUND: Externally caused traumatic brain injury (TBI) poses a woeful worldwide health concern, bringing about disability, death, and prolonged neurological impairment. Increased galectin-3 levels have been linked to unfavorable outcomes in several neurological conditions. This study explores the role of galectin-3 in TBI, specifically examining its contribution to neuroinflammation.
    METHODS: BV2 microglia cells treated with lipopolysaccharide (LPS) and a mouse model of TBI were applied to investigate the impact of galectin-3 on neuroinflammation following TBI. Western blotting and immunofluorescence labeling were applied for evaluating protein levels and colocalization. Adeno-associated virus (AAV) that targets microglia was used to knock down galectin-3 in microglia. Nissl staining and the modified neurologic severity score were employed in evaluating neural survival and neurological function, and the cognitive impairment following TBI was assessed by the Y-Maze and Morri water maze test.
    RESULTS: Galectin-3 expression was shown to rise dramatically after TBI, peaking between days five and seven. In vitro, BV2 cells treated with LPS showed reduced NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation when galectin-3 was inhibited. In LPS-activated microglia, galectin-3 inhibition specifically decreased the expression of Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), p-NF-κB, NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and Gasdermin D (GSDMD). Injection with AAV containing siRNA to knock down galectin-3 in microglia was operated on mice in vivo. Following TBI, this knockdown led to reduced NLRP3 inflammasome activation, neuronal death, neurological impairments and cognitive impairment.
    CONCLUSIONS: Our foundings indicate that modulating microglia-derived galectin-3 following TBI to reduce neuroinflammation could serve as a promising therapeutic strategy.
    Keywords:  Galectin-3; Microglia; NLRP3 inflammasome; Neuroinflammation; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.brainres.2025.149560
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