bims-micgli Biomed News
on Microglia
Issue of 2026–03–22
seventeen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.
  2. Microglial fructose metabolism is essential for glioblastoma growth.
  3. Inflammatory Mediators Both Directly and Indirectly Promote Microglial Proliferation.
  4. Protocol for visualizing microglial lysosomal content by immunohistochemistry in the rodent brain.
  5. Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress.
  6. Genetic inactivation of TRPM4 does not alter the temperature-dependent movement of mouse microglia.
  7. ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
  8. Soluble α2δ-1, altered in disease CSF, modulates network homeostasis and rescues deficits in a neuropsychiatric mouse model.
  9. SYK-dependent lipid handling in monocyte-derived macrophages governs functional recovery after spinal cord injury.
  10. Brain's protective barrier stays leaky for years after playing contact sports.
  11. Single-cell RNA sequencing uncovers neutrophil clusters associated with autoimmune neuroinflammation.
  12. Targeting TREM2 to disentangle neuroinflammation and α-Syn pathological propagation in Parkinson's disease.
  13. A distinct tau oligomer strain defines the molecular and proteomic landscape of rapidly progressive Alzheimer's disease.
  14. Blocking microglial reactivity via purinergic receptors prevents subacute cognitive deficits after TIA.
  15. Single-Nucleus Transcriptomics Reveals Microglial State Transitions and Astrocytic Trajectory Divergence During Glial Remodeling Induced by Intracortical Electrode Implantation.
  16. Microglia cause HIV-induced transcriptional and metabolic changes in human neural organoids.
  17. Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth.
  1. Nat Immunol. 2026 Mar 18.
    Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.
    Maximilian Fliegauf, Damien Levard, Francesco Cardamone, Maximilian Frosch, Siegmar Kuhn, Roman Sankowski, Martino Provinciali, Anaelle Aurelie Dumas, Adrià Dalmau Gasull, Philipp Aktories, Alexander Oschwald, Marius Schwabenland, Rebekka Scholz, Marc D Beyer, Jonas J Neher, Michael Kollefrath, Dimos Baltas, Wilfried Reichardt, Dominik von Elverfeldt, Denis Vivien, Jovana Cupovic, Nicola Iovino, Marina Rubio, Lukas Amann, Marco Prinz.
      Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41590-026-02457-y
  2. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2521256123
    Microglial fructose metabolism is essential for glioblastoma growth.
    Leah K Billingham, Susan L DeLay, Yasmina Eshac, Tzu-Yi Chia, Shashwat Tripathi, Ian E Olson, Kaylee Zilinger, Jay Subbiah, Zhaoquan Wang, Nishanth S Sadagopan, Hinda Najem, Guillaume Cognet, Joshua L Katz, Ruochen Du, Khizar R Nandoliya, Lauren K Boland, Gustavo Ignacio Vázquez-Cervantes, Si Wang, Hanxiao Wan, Allie B Lipshutz, Alina R Murphy, Joseph Duffy, Irina V Balyasnikova, Peng Zhang, Dieter Henrik Heiland, Atique U Ahmed, Catalina Lee-Chang, Amy B Heimberger, Justin S A Perry, Alexander Muir, Navdeep S Chandel, Jason Miska.
      Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.
    Keywords:  fructose metabolism; glioblastoma; microglia; redox homeostasis
    DOI:  https://doi.org/10.1073/pnas.2521256123
  3. Glia. 2026 May;74(5): e70150
    Inflammatory Mediators Both Directly and Indirectly Promote Microglial Proliferation.
    Brady P Hammond, Eugene Hahn, Kelly V Lee, Bradley J Kerr, Jason R Plemel.
      Microglia-the predominant immune cell of the central nervous system (CNS)-possess an astounding capacity for proliferation. In development, this proliferation ensures that microglia are present at a sufficient density to perform their vital functions throughout development and into adulthood. During diseases or following CNS injuries, microglial proliferation similarly promotes an increase in microglial density to respond to damage. However, the governing mechanisms for microglial proliferation remain unknown. While many factors have been suggested to promote microglial proliferation-known as mitogens-or to increase microglial densities both in vitro and in vivo, there has been no standardized comparison of these factors. Here, we screened 22 of these factors in serum-free microglial cultures which more faithfully recapitulate in vivo microglial biology. We confirmed three cytokines-colony stimulating factor-2, interleukin-3 and tumor necrosis factor-ɑ-promote microglia proliferation. We similarly tested the remaining non-mitogenic factors for an indirect ability to regulate microglial proliferation by conditioning media from other CNS cell lineages and measuring the capacity for conditioned media to promote microglial proliferation. Of the tested factors and lineages, only interleukin-1ɑ and interleukin-1β promoted the release of a microglial mitogen from astrocytes, which we confirmed to be CSF2. Together, we demonstrate that in standardized conditions, very few factors that were previously reported to promote microglial proliferation or increase microglial densities, are directly, or indirectly, mitogenic.
    DOI:  https://doi.org/10.1002/glia.70150
  4. STAR Protoc. 2026 Mar 15. pii: S2666-1667(26)00091-2. [Epub ahead of print]7(2): 104438
    Protocol for visualizing microglial lysosomal content by immunohistochemistry in the rodent brain.
    Celeste Laporte, Masha Prager-Khoutorsky.
      Microglia, the resident phagocytes of the central nervous system, clear diverse substrates in development, aging, injury, and disease. Here, we present a protocol to visualize phagocytosed content within microglial lysosomes in the rodent brain using immunohistochemistry and confocal microscopy. We describe the steps for tissue staining, image acquisition, and lysosome analysis. We then detail the procedures for microglia and lysosome reconstruction for 3D visualization. For complete details on the use and execution of this protocol, please refer to Gu et al.1.
    Keywords:  Cell Biology; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2026.104438
  5. J Cell Mol Med. 2026 Mar;30(6): e71074
    Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress.
    Dayoung Kim, Takayuki Kondo, Keiko Imamura, Kayoko Tsukita, Ayako Nagahashi, Tomoki Sakasai, Haruhisa Inoue.
      The APOE gene, which encodes Apolipoprotein E (ApoE), is the strongest genetic risk locus for Alzheimer's disease (AD). A substantial fraction of AD risk genes converges on pathways controlling lipid metabolism and immune regulation, in which microglia serve as a central integrative hub in the brain. Although microglial phenotypes linked to different APOE genotypes have been extensively characterised, the fundamental question of how ApoE shapes the core functions of human microglia remains unresolved. Here, we generated APOE knockout (KO) microglia from AD patient-derived induced pluripotent stem cells (iPSCs) and characterised their cellular and molecular phenotypes. Ablation of APOE resulted in marked lipid droplet accumulation and increased NLRP3 inflammasome activation. Transcriptomic analysis further revealed downregulation of cell cycle-related pathways, accompanied by enrichment of an oxidative stress-associated pathway. Consistent with these transcriptomic signatures, APOE KO microglia exhibited elevated intracellular reactive oxygen species (ROS) levels and a marked reduction in proliferative capacity. Given the importance of microglial proliferation for maintaining immune homeostasis in the brain, our findings highlight ApoE as being an important regulator of this process, with potential consequences for the pathogenesis of neurodegenerative disorders.
    Keywords:  ApoE; TGF‐β signalling; cell cycle; iPSCs; inflammasome; lipid; microglia; oxidative stress; proliferation
    DOI:  https://doi.org/10.1111/jcmm.71074
  6. J Physiol Sci. 2026 Mar 10. pii: S1880-6546(26)00013-2. [Epub ahead of print]76(2): 100067
    Genetic inactivation of TRPM4 does not alter the temperature-dependent movement of mouse microglia.
    Rei Nishimoto, Yoshikazu Matsuoka, Makoto Tominaga.
      Temperature sensing shapes behavior and cellular functions, yet the molecular basis of thermosensitivity in non-neuronal cells remains poorly defined. Microglia are resident immune cells of the central nervous system that help maintain brain homeostasis via immune surveillance and injury responses. We previously showed that microglial motility is temperature dependent and is largely mediated by the thermosensitive ion channel transient receptor potential vanilloid 4 (TRPV4), a thermosensitive ion channel. However, the contribution of transient receptor potential melastatin 4 (TRPM4) is unclear because suitable Trpm4 mutant mice were not available in our earlier work. Here, we generated functional Trpm4-knockout mice (TRPM4KO) using CRISPR/Cas9 genome editing based on a published strategy. Time-lapse imaging of primary microglia across a range of temperatures revealed that Trpm4 deficiency did not alter temperature-dependent motility in vitro. These results indicate that TRPM4 is dispensable for temperature-dependent microglial motility.
    Keywords:  Microglia; TRP channels; Thermosensitivity
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100067
  7. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2534066123
    ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
    Ziqi Zou, Jiajie Zhou, Yanhua Lu, Yuting Huang, Linru Zhou, Xiaoyu Wang, Jiahui Chen, Hengrui Tian, Xinnuo Ge, Chenyao Guo, Weiran Yao, Xiaosheng Zheng, Jia He, Yue Du, Yiting Zhou, Yinjing Song, Wei Luo, Qingqing Wang, Jun-Ping Liu, Meng Xia.
      Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.
    Keywords:  ATP13A2 mutation; NLRP3 inflammasome; Parkinson’s disease; macrophage; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2534066123
  8. Neuron. 2026 Mar 19. pii: S0896-6273(26)00087-5. [Epub ahead of print]
    Soluble α2δ-1, altered in disease CSF, modulates network homeostasis and rescues deficits in a neuropsychiatric mouse model.
    Marc Dos Santos, Marc P Forrest, Ewa Bomba-Warczak, Soumil Dey, Euan Parnell, Jessica M Christiansen, Seby L Edassery, Kun Yang, Lindsay N Hayes, Jennifer M Coughlin, Blair L Eckman, Catherine R Lammert, M Dolores Martin-de-Saavedra, Maria V Barbolina, Marco Martina, Akira Sawa, Jeffrey N Savas, Peter Penzes.
      Excitation-inhibition (E/I) balance depends on dynamic communication between neuronal subtypes, potentially beyond classical neurotransmission. While membrane-bound ion channels are essential for neuronal function, their potential roles as extracellular regulators of network dynamics remain largely unexplored. Here, we identify a soluble form of the voltage-gated Ca2+ channel subunit α2δ-1 in human cerebrospinal fluid (CSF) and show that it acts as an activity-regulated intercellular modulator of network homeostasis. Soluble α2δ-1 is reduced in the CSF of individuals with schizophrenia (SZ). Its synthetic analog, synthetic ectodomain of Alpha2Delta-1 (SEAD1), modulates cortical activity by enhancing the function of parvalbumin-positive (PV+) interneurons and restoring E/I balance. A single SEAD1 injection into the prefrontal cortex of a genetic mouse model of SZ reversed synaptic and behavioral deficits, including memory and social impairments. These findings reveal soluble synaptic ectodomains as a previously underappreciated class of extracellular signaling molecules with therapeutic potential in neuropsychiatric disorders.
    Keywords:  cerebrospinal fluid; intercellular communication; neuronal network homeostasis; neuropsychiatric disorders; synaptic ectodomains
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.004
  9. Brain Res Bull. 2026 Mar 12. pii: S0361-9230(26)00109-7. [Epub ahead of print]237 111823
    SYK-dependent lipid handling in monocyte-derived macrophages governs functional recovery after spinal cord injury.
    Yuanzhe Zhao, Hao Hu, Jingwen Wang, Yixue Hu, Linhan Yang, Zhonghan Wu, Shangkun Zhao, Xuezi Wang, Yiyang Mu, Meige Zheng, Dasheng Tian, Li Cheng.
      After spinal cord injury (SCI), monocyte-derived macrophages and resident microglia play critical, yet potentially distinct, roles in sculpting the lesion milieu via phagocytosis. However, the underlying mechanisms remain unclear. While spleen tyrosine kinase (SYK) has emerged as a master switch for microglial neuroprotection, its function in macrophages after SCI is unknown. Here, we show that SYK expression increases after SCI, peaking at 7 days post-injury (dpi) and persisting until 28 dpi, predominantly within Cx3cr1-GFP-F4/80+ macrophages rather than Cx3cr1-GFP+F4/80- microglia. Pharmacological blockade of SYK with intraperitoneal Entospletinib impaired macrophage phagocytosis, triggered intracellular lipid droplet accumulation, and impeded axonal regrowth and functional recovery. Conversely, SYK agonism with Pustulan injection boosted myelin phagocytosis, accelerated lipid metabolism, and enhanced locomotor outcomes. Notably, in triggering receptor expressed on myeloid cell 2 (TREM2) knockout mice, Pustulan treatment restored macrophage phagocytic competence and lipid droplet clearance, identifying TREM2-SYK signaling as the critical axis governing post-SCI macrophage function. Our findings establish SYK as a therapeutic target for reprogramming macrophage lipid metabolism and promoting repair following SCI.
    Keywords:  Lipid metabolism; Macrophage; Phagocytosis; Spinal cord injury; Spleen tyrosine kinase
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111823
  10. Nature. 2026 Mar 18.
    Brain's protective barrier stays leaky for years after playing contact sports.
    Max Kozlov.
      
    Keywords:  Brain; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-00885-2
  11. J Neuroinflammation. 2026 Mar 18.
    Single-cell RNA sequencing uncovers neutrophil clusters associated with autoimmune neuroinflammation.
    Yong Wang, William J Turbitt, Lianna Zhou, Zhaoqi Yan, Sweta B Patel, Wei Yang, Zhang Li, Jessica A Buckley, Grace Mulia, Robert S Welner, William R Meador, Chander Raman, Hongwei Qin, Etty N Benveniste.
      
    Keywords:  Brain-targeted Experimental Autoimmune Encephalomyelitis (btEAE); Neutrophils; Serum Amyloid A3 (SAA3); Single-cell RNA Sequencing (scRNA-Seq); Suppressors Of Cytokine Signaling 3 (SOCS3)
    DOI:  https://doi.org/10.1186/s12974-026-03772-9
  12. Cell Signal. 2026 Mar 13. pii: S0898-6568(26)00136-1. [Epub ahead of print] 112485
    Targeting TREM2 to disentangle neuroinflammation and α-Syn pathological propagation in Parkinson's disease.
    Yixu Chen, Hao Wang, Jun Wang, Jianshe Wei.
      Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) that predominantly affects middle-aged and elderly populations, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation of α-synuclein (α-Syn) as its core pathological features. Its pathogenesis is complex, and the crosstalk among genetic factors, microenvironmental factors and neuroinflammation has emerged as a central research focus at present. Triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, is deeply implicated in the pathophysiological processes of PD by mediating multiple biological events, including phagocytic clearance, inflammatory homeostasis, autophagy regulation and neuronal repair. In recent years, Advances in genomics, cell biology and model animal technologies, the genetic association between TREM2 gene variants and PD, the regulatory role of the TREM2 signaling pathway in α-Syn pathological propagation, and its dual effects in neuroinflammation and dopaminergic neuron protection have been gradually elucidated. This review systematically summarizes the molecular structure and signal transduction mechanisms of TREM2, with a focus on elaborating the multidimensional roles of the TREM2 signaling pathway in the regulation of α-Syn metabolism, microglial polarization, dopaminergic neuron survival and non-motor symptoms in PD. We also conduct an in-depth analysis of the pathological significance of TREM2 gene variants and their interactive effects with microenvironmental factors, and discuss therapeutic strategies and research progress for PD targeting the TREM2 signaling pathway. Finally, we summarize the current research controversies and future directions, aiming to provide new insights into the mechanistic investigation and precision therapy of PD.
    Keywords:  Microglia; Neuroinflammation; Parkinson's disease; TREM2; Α-Synuclein
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112485
  13. Acta Neuropathol. 2026 Mar 18. pii: 27. [Epub ahead of print]151(1):
    A distinct tau oligomer strain defines the molecular and proteomic landscape of rapidly progressive Alzheimer's disease.
    Tayyaba Saleem, Wiebke Möbius, Matthias Schmitz, Angela da Silva Correia, Carolina Thomas, Sezgi Canaslan, Peter Hermann, Stefan Göbel, Saima Zafar, Elisabeth Root, Christine Stadelmann, Olivier Andreoletti, Michael Hoppert, Tiago Fleming Outeiro, Isidre Ferrer, Neelam Younas, Inga Zerr.
      Rapidly progressive Alzheimer's disease (rpAD) is a rare subtype with rapid decline, but its molecular underpinnings remain poorly defined. Here, brain-derived tau oligomers (TauO) were systematically compared across nondemented controls, slowly progressive AD (spAD), and rpAD to test whether subtype-specific TauO signatures align with clinical aggressiveness. TauO were immunoprecipitated from frontal cortex using T22 antibody and characterized by Western blotting, transmission electron microscopy, label-free quantitative proteomics, and SH-SY5Y toxicity assays, complemented by longitudinal analysis of tau phosphorylation in inoculated 3xTg AD mice. T22-positive high-molecular-weight TauO were successfully enriched from all groups, where rpAD TauO exhibited compact, densely packed oligomers under TEM and the highest phosphorylation at pS396 and pS422, exceeding both spAD and controls (p ≤ 0.0327). In 3xTg mice, pS396 showed an early increase followed by a late decline, consistent with dynamic shifts in tau solubility during disease evolution. Brain-derived TauO from spAD and rpAD, but not recombinant tau monomers or control-derived TauO, significantly reduced SH-SY5Y cell viability. Proteomic profiling identified 2388 TauO-associated proteins, including a shared 556-protein core and a striking expansion of rpAD-unique interactors (n = 1101). In controls and spAD, the core TauO interactome was enriched for translation, proteostasis, mitochondrial respiration, and vesicle-trafficking pathways, whereas these modules were absent in rpAD. Instead, rpAD TauO showed selective enrichment of aldehyde detoxification, amino-acid and carbon metabolism, and actin-regulatory modules, alongside increased association of SERPINA1, ALDH9A1, MAPRE3, DPYSL2, DPYSL3, and NFASC and reduced coupling to mitochondrial (MRPL17) and complement (C9) components. These convergent structural, post-translational, toxic, and interactome changes indicate that rpAD is defined by a biochemically distinct TauO species embedded in a metabolic and cytoskeleton-focused network, providing a mechanistic framework for its aggressive clinical course and a basis for subtype-specific biomarker and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Protein aggregation; Proteomics; Rapidly progressive Alzheimer’s disease; Tau oligomers
    DOI:  https://doi.org/10.1007/s00401-026-02998-4
  14. EMBO Mol Med. 2026 Mar 20.
    Blocking microglial reactivity via purinergic receptors prevents subacute cognitive deficits after TIA.
    Gemma Llovera, Steffanie Heindl, Daniel P Varga, Nikolett Lenart, Sebastian Kallabis, Vanessa Göb, David Stegner, Raphael Escaig, Leo Nicolai, Nicolai Franzmeier, Felix Meissner, Adam Denes, Arthur Liesz.
      Our research presents a new animal model of transient ischemic attack (TIA) that mimics brief episodes without cell loss, but results in neuronal and behavioral deficits. We identified excessive microglial reactivity, driven by acute ATP release, as a key factor in post-TIA neurological deficits, which were ameliorated by inhibiting the P2Y12 receptor, a microglia-specific purinergic receptor in the brain parenchyma responsible for activity-dependent microglial cell-cell interactions. This finding suggests that modulation of microglial reactivity offers a promising strategy to prevent cognitive impairment in TIA patients, opening avenues for future research in this underexplored area.
    Keywords:  ATP; Microglia; Purinergic Receptor; Synapse; TIA
    DOI:  https://doi.org/10.1038/s44321-026-00397-6
  15. Glia. 2026 May;74(5): e70148
    Single-Nucleus Transcriptomics Reveals Microglial State Transitions and Astrocytic Trajectory Divergence During Glial Remodeling Induced by Intracortical Electrode Implantation.
    Zhi Zhao, Xiaoge Duan, Hanjun Huang, Yuxue Zhang, Meiting Wang, Jiaoqin Qin, Sen Lin, Hailan Chen.
      The foreign body response to intracortical electrodes, characterized by chronic neuroinflammation and glial scar formation, remains a primary cause of long-term functional failure. However, neurons and glial cells' heterogeneity and intercellular signaling mechanisms following electrode implantation remain poorly resolved, which is responsible for direct dysfunction. Here, we applied single-nucleus RNA sequencing (snRNA-seq) to profile the peri-implant microenvironment in rat motor cortex tissue at 3, 25, and 50 days post-electrode implantation. Integrated bioinformatic analyses, including clustering, pseudotemporal trajectory reconstruction, and cell-cell communication inference, revealed a coordinated cellular response. We identified a pathologic microglial subpopulation (marked by Gpnmb, SPP1, and CD63) and a scar-associated astrocytic subtype (characterized by Mctp1 and Lrrc7) that progressively dominate the peri-implant niche. Crucially, we reveal that neurons orchestrate these processes via CX3CL1-CX3CR1 signaling, modulating microglial polarization and PTN-ALK/Ptpprz1 interaction, promoting astrogliosis and scar formation. These findings define the dynamic neuron-glia signaling landscape surrounding chronically implanted electrodes and provide mechanistic insight into how modulating cell-cell communication may improve the long-term biocompatibility of neural interfaces.
    Keywords:  biocompatibility; brain‐computer interfaces; inflammatory tissue response; intracortical electrodes; single‐nucleus RNA sequencing
    DOI:  https://doi.org/10.1002/glia.70148
  16. Commun Biol. 2026 Mar 19.
    Microglia cause HIV-induced transcriptional and metabolic changes in human neural organoids.
    Pamela E Capendale, Leanne C Helgers, Anoop T Ambikan, Renata Vieira de Sá, Katja C Wolthers, Teunis B H Geijtenbeek, Adithya Sridhar, Ujjwal Neogi, Dasja Pajkrt.
      Human immunodeficiency virus (HIV) can invade the central nervous system during the initial stages of infection and contribute to HIV-associated neurocognitive disorder, affecting up to 50% of people living with HIV (PLWH). To investigate HIV-1-induced immunometabolic changes in the brain, we used a three-dimensional microglia-embedded human neural organoid model. Transcriptomic analysis and genome-scale metabolic modeling revealed that HIV-1 infection led to more pronounced transcriptional changes in the presence of microglia, including upregulation of pro-inflammatory pathways. We identified CCR6, important for HIV-1 permissiveness, to be significantly upregulated upon infection. Metabolic analysis showed increased expression in metabolite transport-related genes, including solute carrier (SLC) genes and altered amino acid metabolism, particularly involving arginine, proline, and tyrosine. These microglia-driven immunometabolic changes may contribute to neuronal dysregulation and, subsequently, neurological complications, which are often observed in PLWH. Early detection of these alterations could support timely therapeutic intervention to improve HIV-related neurologic insult.
    DOI:  https://doi.org/10.1038/s42003-026-09864-9
  17. J Immunol. 2026 Mar 17. pii: vkag026. [Epub ahead of print]215(3):
    Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth.
    Anthony Cannon, Jilu Zhang, James Ropa, Abigail Pajulas, Cherry C L Cheung, Michelle Liu Niese, Ahmed M Abdelaal, Sabrina Khan, Emily Bromley, Gyoyeon Hwang, Maya Krishnan, Basar Bilgicer, Teresa L Mastracci, Daniella Muallem Schwartz, Mark H Kaplan.
      Tumor-associated macrophages are an abundant, tumor-infiltrating cell population that supports the evasion of tumor cells from antitumoral immune cell detection by generating an immunosuppressive tumor-immune microenvironment (TIME). The immunosuppressive function of macrophages is dictated by the cytokine environment. IL-9 is a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab previously identified a protumoral role of IL-9 by expanding lung interstitial macrophage (IM) populations and inducing the expression of arginase 1 (ARG1) to enhance tumor growth. However, the underlying mechanism by which IL-9 receptor/ARG1+ IMs promote tumor progression remains incomplete. Here, we demonstrate that macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and reduce protumor arginine-derived metabolite production. Furthermore, using bulk RNA sequencing of lung macrophages isolated from Il9r-/-:wild-type mixed-bone marrow chimeric mice, we demonstrate that IL-9 intrinsically alters the transcriptomic landscape of lung IMs. Mechanistically, IL-9 promotes intrinsic Arg1 expression through an IRF4-dependent regulatory pathway and modulates arginine and polyamine concentration within IMs and lung tissue, resulting in increased lung tumor growth and altered macrophage phenotypes. Thus, our work defines a protumor function of IL-9-responsive macrophages mediated by altered intrinsic arginine metabolism in lung IMs that enhances lung tumor growth.
    Keywords:  ARG1; IL-9; arginine metabolism; interstitial macrophages; polyamines
    DOI:  https://doi.org/10.1093/jimmun/vkag026
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