bims-microg 2026-11-01 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–11–01
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Microglial NUS1 deficiency drives dopaminergic neurodegeneration through intercellular iron dysregulation in Parkinson's disease models.
Serotonin signaling enhances phagocytosis by brain macrophages through Htr2b and alleviates brain injury after stroke.
Chronic progressive demyelination induces a microglial state with lysosomal dysfunction.
Spatial multi-omics reveals disease-associated oligodendrocytes and metabolic dysregulation in male Parkinson's disease mouse models.
Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors in mice.
Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.
An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline.
Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis.
Glioma-derived ULBP2 triggers microglial extracellular traps formation via PAD4 lactylation to drive autophagy-dependent malignant growth.
Repopulated microglia promote regulatory T cell accumulation and spinal cord injury repair in mice.
Microglial deletion induces despair-like behavior associated with astrogliosis.
Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization.
Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson's disease via the tim-3/NF-κb axis.
sox17 Mutagenesis Reveals Compounding Effects ofMaternal and Zygotic Contribution on Microglia Abundance.
Single-cell transcriptomics reveals reversible microglia/macrophage activation after human retinal neuron transplantation into mouse retina.
β-Glucan Pretreatment Attenuates Single Prolonged Stress-Associated Behavioural and Neuroinflammatory Changes in Male Mice.
A Human iPSC-Derived Tri-Culture Model of NeuroHIV: HIV Infection, Antiretroviral Drug Effects, Microglial Morphology, and Neuronal Calcium Dynamics.
Mxd1-mediated transcriptional repression of FTO induces NLRP3-dependent pyroptosis in retinal microglia.

Nat Neurosci. 2026 Oct 26.

Microglial NUS1 deficiency drives dopaminergic neurodegeneration through intercellular iron dysregulation in Parkinson's disease models.

Lele Liu, Yan Hong, Xiying Wang, Xiurong Huang, Yanni Ma, Rui Wang, Qian Sun, Hongyang Sun, Zongbing Hao, Chenchen Mu, Xiaojun Lu, Lifang Hu, Jifeng Guo, Beisha Tang, Guanghui Wang, Haigang Ren.

The selective loss of dopaminergic neurons in the substantia nigra pars compacta is a defining feature of Parkinson's disease (PD), yet its underlying mechanisms remain unclear. NUS1, which encodes neurite outgrowth inhibitor-B receptor (NgBR), was recently identified as a PD risk gene. Here we show that NgBR is highly expressed in microglia, where its deficiency drives progressive PD-like motor deficits and dopaminergic neurodegeneration via the LCN2-SLC22A17 iron-transport axis in mice. NgBR deficiency in mouse and human microglia triggers endoplasmic reticulum stress and PERK-ATF4-NUPR1 signaling, which preferentially induces LCN2-mediated iron efflux over cytokine release. Subsequently, microglia-derived iron-loaded Holo-LCN2, but not iron-free Apo-LCN2, is internalized by SLC22A17, a receptor highly expressed in dopaminergic neurons, leading to iron overload and ferroptosis. Pharmacological inhibition of LCN2-SLC22A17 axis or ferroptosis alleviated dopaminergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo. Our findings identify disrupted intercellular iron homeostasis as a pathological driver of PD and highlight the LCN2-SLC22A17 axis as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41593-026-02499-3
Nat Neurosci. 2026 Oct 28.

Serotonin signaling enhances phagocytosis by brain macrophages through Htr2b and alleviates brain injury after stroke.

Yueman Zhang, Yonghui Chen, Yue Cheng, Ruqi Li, Weijie Chen, Yan Li, Qiuyue Fan, Yuxi Zhou, Tingting Huang, Wanqing Xie, Yunlu Guo, Arthur Liesz, Jieqing Wan, Florent Ginhoux, Peiying Li.

Brain myeloid cells, including infiltrating monocyte-derived macrophages (MDMs) and microglia, play critical roles in ischemic brain injury, clearing debris and shaping neuroinflammation and neurological outcomes. Yet the underlying mechanisms remain unclear. Here, using single-cell RNA sequencing and fate mapping with an MDM-specific Ms4a3creERT2-Ai14 mouse line, we identified serotonin receptor Htr2b+ MDMs as a crucial cell population involved in resolving neuroinflammation within the ischemic penumbra. Htr2b+ MDMs significantly accumulate in the peri-infarct region and exhibit enhanced phagocytosis and inflammation-resolving gene signatures. Mechanistically, Htr2b activation promotes nuclear translocation of Tfe3, a key lysosomal regulator, enhancing lysosomal biogenesis and supporting phagocytic activity. MDM-specific Htr2b ablation impairs debris clearance, exacerbates neuroinflammation and ischemic injury, whereas pharmacological agonism or Tfe3 activation restores lysosomal biogenesis in brain MDMs and improves post-stroke outcomes. Thus we demonstrate a previously unrecognized Htr2b+ MDM subset that integrates serotonin signaling to license intrinsic phagocytic function, alleviating ischemic brain injury.

DOI: https://doi.org/10.1038/s41593-026-02482-y
Nat Neurosci. 2026 Oct 26.

Chronic progressive demyelination induces a microglial state with lysosomal dysfunction.

Stefan A Berghoff, Lena Spieth, Simona Vitale, Lennart Schlaphoff, Martin Zirngibl, Niklas Junker, Alan-Charles Dean, Lu Liu, Alkmini Damkou, Stefan Roth, Charlene-Annett Hurler, Leon Hosang, Katrin Perez Anderson, Simon Besson-Girard, Marvin Reich, Astrid Feiten, Ludwig Huber, Christoph Müller, Georg Kislinger, Lina Dinkel, Yakum B Nkeh, Janos Groh, Anna Williams, Arthur Liesz, Martina Schifferer, Gesine Saher, Klaus-Armin Nave, Sarah Jäkel, Sabina Tahirovic, Martin Giera, Ozgun Gokce, Mikael Simons.

Dysfunctional immune responses impair remyelination and contribute to neurodegeneration. While immune and metabolic responses to acute myelin injury are well characterized, myeloid cell adaptations to chronic myelin damage remain poorly understood. Here we performed a comparative analysis of genetic and toxic mouse models of acute and chronic demyelination, which identified a distinct microglial state associated with chronic demyelination, characterized by sustained pro-inflammatory activation, lysosomal lipid sequestration and reduced lipid droplet formation. Transcriptomics profiling further revealed a metabolic program marked by upregulated cholesterol synthesis and diminished sterol efflux. Treatment with a desmosterol mimetic possessing 24-dehydrocholesterol reductase inhibitor activity reversed this microglial state, attenuated pro-inflammatory signaling (including C-C Motif Chemokine Ligand 4 expression), reduced myelin damage and improved motor performance in a mouse model of leukodystrophy. Our findings uncover a pro-inflammatory microglial state characterized by lysosomal dysfunction and increased myelin reactivity, highlighting a novel therapeutic target for chronic demyelinating disorders.

DOI: https://doi.org/10.1038/s41593-026-02489-5
Nat Commun. 2026 09 25. pii: 11151. [Epub ahead of print]17(1):

Spatial multi-omics reveals disease-associated oligodendrocytes and metabolic dysregulation in male Parkinson's disease mouse models.

Ziting Zhu, Zongtang Xu, Minshan Chen, Liuyan Ding, Du Feng, Fengchu Liang, Hui Shu, Zhongqiang Su, Xingting Huang, Xiaoqin Zhu, Xiaolei Liang, Shuxuan Huang, Pingyi Xu, Wenlong Zhang.

Parkinson's disease involves progressive α-synuclein pathology, but how this reshapes the brain's spatial immunometabolic landscape, and how oligodendrocytes participate, remain incompletely defined. Here we combine single-nucleus RNA sequencing, spatial transcriptomics and spatial metabolomics in male A53T α-synuclein transgenic mice across disease stages, together with male mice carrying adeno-associated virus-mediated α-synuclein overexpression, human midbrain and cerebrospinal fluid samples. We describe a disease-associated oligodendrocyte lineage marked by elevated Il33 and Kirrel3 that expands with pathology in both mouse models. Interleukin 33 is upregulated in oligodendrocytes and its receptor ST2 in microglia, and bidirectional manipulation of oligodendrocyte Il33 alters microglial ST2 activation, insoluble α-synuclein burden and motor performance. In the substantia nigra and ventral tegmental area, transcriptomic and metabolomic changes converge on lipid- and glutamate-related pathways. Both proteins are also elevated in human Parkinson's disease midbrain and cerebrospinal fluid. These data implicate oligodendrocyte interleukin 33-ST2 signalling and provide a spatially resolved resource.

DOI: https://doi.org/10.1038/s41467-026-78051-5
Nat Commun. 2026 09 26. pii: 11156. [Epub ahead of print]17(1):

Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors in mice.

Michael W Gongwer, Fanny Etienne, Eric N Moca, Sara V Blagburn-Blanco, Megan S Chappell, Keionna A Newton, Daniel T Gray, Jack P Riley, Chloe R Christensen, Russell N Ahmed, Alexander S Enos, Melody Haratian, Alex Qi, Rocio Rojo, Scott A Wilke, Clare Pridans, Laura A DeNardo, Lindsay M De Biase.

While microglia are well known for pruning synapses during neurodevelopment, their role in synapse formation remains understudied. Here we investigate how microglial absence impacts synaptic development in the nucleus accumbens (NAc), a region critical for emotional regulation and motivated behaviors. Using genetically modified mice lacking microglia (Csf1rΔFIRE/ΔFIRE), we find blunted excitatory synapse formation in the NAc, particularly during the second and third postnatal weeks. Tissue-level NAc proteomics in the third postnatal week reveals changes in proteins involved in synapse structure, trans-synaptic signaling, and pre-synaptic function. Although electrophysiological changes largely resolve by adulthood, microglia-lacking mice exhibit persistent changes in threat avoidance behavior and underlying NAc neuronal activity. Transient depletion of NAc microglia during the second postnatal week similarly disrupts synapse formation and adult threat avoidance. Together, these findings identify a role for microglia in shaping NAc synaptic development and in establishing functional circuits that support adult behavioral function.

DOI: https://doi.org/10.1038/s41467-026-77487-z
Adv Sci (Weinh). 2026 Oct 28. pii: e78509. [Epub ahead of print]

Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.

Jizhou Zhang, Tsz Kwan Yau, Joyce Tse, Tsz Ho Li, Dongjie Hu, Yong Juan Zhao, Ting-Fung Chan.

  The molecular mechanisms linking type 2 diabetes to increased neurodegenerative risk remain poorly defined. Given the critical involvement of microglial dysfunction in neurodegeneration, we constructed a temporal single-cell atlas integrating transcriptomic and epigenomic profiles of microglia from diabetic (db/db) and control (db/m) mice across the lifespan. We delineated a nonlinear, diabetes-specific pathological trajectory characterized by early inflammatory activation, a mid-stage inflection in neurodegeneration-associated signaling and metabolic stress, and late-stage dysfunction. Chromatin accessibility profiling revealed early and persistent epigenomic priming of neurodegeneration-associated pathways, accompanied by stage-specific enhancer rewiring. Pseudotime analysis identified a disease-associated microglial (DAM) state as a candidate transition node, characterized by biased polarization and accelerated maturation under diabetic conditions. Targeted validation using freshly isolated microglia and primary microglial cultures further supported the early expansion of the DAM population, a bias toward homeostatic-to-DAM activation, and Arhgap15-dependent regulation of phagocytic activity. Together, these findings identify microglial states and candidate regulatory pathways that may link diabetes to neurodegenerative vulnerability.

Keywords:  diabetes; microglia; neurodegeneration; single‐cell multi‐omics

DOI:  https://doi.org/10.1002/advs.202600023
Sci Adv. 2026 Oct 30. 12(44): eaee0110

An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline.

Jin Li, Zhen-He Wang, Jia-Xin Pan, Zhe-Li Jiang, Rui Li, Xu-Fan Gao, Gang Sheng, Zi-Hui Wang, Ya-Qing Ma, Zheng-Lu Wang, Ting Wang, Ran Huan, Lv-Tao Zeng, Wei Zhang, Da-Peng Dai, Ju Cui, Xiao-Yang Zhou, Li-Qun Zhang, Wen Su, Hai-Bo Chen, Guo-Xin Hu, Ruo-Mei Qi, Jian-Ping Cai.

Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.

DOI: https://doi.org/10.1126/sciadv.aee0110
J Exp Med. 2026 Dec 07. pii: e20260104. [Epub ahead of print]223(12):

Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis.

Adeline E Walsh, Benjamin A Davis, Joshua D Samuels, William A Mills, Jessica M Thanos, Alexis M Johnson, Katelyn A Moore, Michael A Puchalski, Eric J Steacy, Benjamin W Wendell, Amélie Daugherty-Lopès, Adrian A Shimpi, Ukpong B Eyo, John R Lukens.

Recent genome-wide association studies have identified numerous Alzheimer's disease (AD) risk genes enriched in microglia, including Crk-associated substrate (Cas) scaffold protein family member 4 (CASS4), which encodes the adaptor protein CASS4. Despite its strong genetic association with AD, the role of CASS4 in disease remains poorly understood. Here, we show that full-body Cass4 deletion in 5xFAD mice increases amyloid-β (Aβ) deposition, neuronal dystrophy, and cognitive deficits. Since microglia are the predominant brain-resident cells expressing Cass4, we investigated its role in microglial responses to Aβ pathology. Loss of CASS4 impaired microglial mobilization to Aβ plaques and reduced plaque compaction. Phosphoproteomic analysis of purified microglia revealed marked disruption of focal adhesion signaling following Cass4 deletion. Consistent with this, CASS4 deficiency abrogated in vivo microglial recruitment to injury and in vitro wound healing responses, two processes that are centrally orchestrated by focal adhesion biology. Together, these findings identify CASS4 as a critical regulator of microglial function and focal adhesion biology and suggest that CASS4 may represent a therapeutic target for AD.

DOI: https://doi.org/10.1084/jem.20260104
Oncogene. 2026 Oct 25.

Glioma-derived ULBP2 triggers microglial extracellular traps formation via PAD4 lactylation to drive autophagy-dependent malignant growth.

Ping Ma, Xiang Zhang, Jinghong Yang, Guanjian Zhao, Luping Xiao, Yuan Cheng, Jianhe Yue, Ning Huang.

The microglial extracellular traps(MiETs) were appeared in glioblastoma multiforme (GBM), but the underlying molecular mechanisms and functions were unknown. In this study, we aimed to explore the ability of GBM-derived UL16-binding protein 2 (ULBP2) on activating MiETs and manipulating microglia to support GBM development. Herein, ULBP2 was identified as a key upregulated protein in GBM and triggered MiETs formation. In turn, MiETs accelerated GBM malignant growth. Mechanistically, GBM released ULBP2 to connect with syndecan-1(SDC1) on microglia, the ULBP2/SDC1 complex induced lactylation of peptidylarginine deiminase 4 (PAD4) and following MiETs formation. Furthermore, MiETs stimulated GBM autophagy to promote proliferation and invasion. Our results demonstrated that GBM exerted a crucial role in MiETs formation through the ULBP2/SDC1/PAD4-Kla axis, and the interaction between GBM and microglia created a feed-forward mechanism for tumor progression. Thus, these data provided novel insights into a potential therapeutic target toward MiETs for preventing and suppressing GBM.

DOI: https://doi.org/10.1038/s41388-026-04031-0
Neural Regen Res. 2026 Oct 29.

Repopulated microglia promote regulatory T cell accumulation and spinal cord injury repair in mice.

Shiyuan Xue, Die Hu, Yijing Liu, Yan Xiao, Qiling Jiang, Xinyi Wei, Jince Zhou, Han Li, Chao Qi, Haitao Fu.

   ABSTRACT: Spinal cord injury causes severe neurological dysfunction, largely driven by secondary injury processes, including neuroinflammation. As the resident immune cells of the central nervous system, microglia can rapidly repopulate throughout the central nervous system following depletion. Regulatory T cells, key mediators of inflammation resolution, also play important roles in tissue repair. However, whether microglial repopulation contributes to spinal cord injury repair and whether Tregs participate in this process remain unclear. Here, we established a microglial depletion-repopulation model using a colony-stimulating factor 1 receptor inhibitor and investigated the role of repopulated microglia in mice with spinal cord injury. Microglial repopulation significantly improved locomotor recovery, gait coordination, and bladder function after spinal cord injury. Histological assessments showed that microglial repopulation reduced lesion size, inhibited apoptosis, increased neuronal survival, and improved axonal integrity. Notably, microglial repopulation increased Treg accumulation and suppressed the release of proinflammatory factors in the injured spinal cord. Consistently, Treg depletion markedly attenuated the neuroprotective and functional benefits induced by microglial repopulation. These findings identify microglial depletion-repopulation as a potential experimental strategy for promoting repair after spinal cord injury.

Keywords:  PLX3397; colony-stimulating factor 1 receptor; functional recovery; immune microenvironment; microglial repopulation; neuroinflammation; neuroprotection; regulatory T cells; spinal cord injury; tissue repair

DOI:  https://doi.org/10.4103/NRR.NRRONLINE-D-26-00915
Transl Psychiatry. 2026 Jul 29. pii: 583. [Epub ahead of print]16(1):

Microglial deletion induces despair-like behavior associated with astrogliosis.

Xun Wang, Shi-Han Liao, Nan Wang, Ya-Ting Chen, Rui-Han Huang, Di-Ji Li, Wen-Ying Jiang, Xiao-Wen Li, Tian-Ming Gao, Jian-Ming Yang.

Microglia, the brain's resident immune cells, are increasingly recognized as key regulators of brain physiology and behavior. However, their specific role in affective states remains controversial, with studies reporting conflicting depression-like outcomes following their removal. Using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 in adult mice of both sexes, we found that microglial deletion selectively induced despair-like behavior (increased immobility in the forced swim test and the tail suspension test) in either sex, without affecting locomotion, anxiety, sociability, anhedonia, or cognition. This effect was accompanied by reactive astrogliosis in the medial prefrontal cortex (mPFC). Unexpectedly, microglial deletion induced a predominant A2-like astrocyte reactivity. Notably, both the despair-like and A2-like phenotypes resolved upon microglia repopulation. Critically, pharmacological inhibition of these hyperactive mPFC astrocytes with fluorocitrate reversed the despair-like phenotype, indicating that microglial loss triggers maladaptive astrocyte reactivity that drives behavioral despair. Our results reveal an essential role for microglia in maintaining emotional homeostasis, possibly through interaction with astrocytes.

DOI: https://doi.org/10.1038/s41398-026-04325-7
Neurotherapeutics. 2026 Oct 26. pii: S1878-7479(26)00281-3. [Epub ahead of print]24(1): e01111

Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization.

Xinyi Ma, Xueying Wang, Lutong Yue, Keyang Duan, Yuchen Hao, Xian'ge Liu, Tao Sun.

  Diabetic neuropathic pain (DNP) is a common and intractable complication of diabetes with limited therapeutic options. Distinct from traditional NF-κB or MAPK inflammatory pathways, resolvin D2 (RvD2) alleviates DNP through metabolic reprogramming-a novel mechanism that remains largely unexplored. Untargeted metabolomics analysis of the spinal cord from DNP model mice and RvD2-treated mice revealed significant alterations in fatty acid oxidation (FAO)-related metabolites between the two groups. Functionally, RvD2 effectively alleviated hyperalgesia in DNP mice and ameliorated the FAO dysfunction associated with a pro-inflammatory microglial state. Mechanistically, RvD2 upregulated the expression of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1a (CPT1a), thereby activating the PPARα/CPT1a axis to enhance FAO. This metabolic shift consequently augmented ATP production, suppressed reactive oxygen species (ROS) levels, and diminished succinate accumulation, which in turn blocked hypoxia-inducible factor-1α (HIF-1α)-mediated pro-inflammatory signaling. Concurrently, RvD2 elevated the acetyl-CoA pool, promoting histone acetylation and chromatin accessibility at the promoters of pro-resolving polarization-related genes, which drove microglia toward a pro-resolving phenotype. Notably, the specific CPT1a inhibitor etomoxir partially reversed these protective effects of RvD2. In conclusion, RvD2 alleviates DNP by driving microglial pro-resolving polarization through a CPT1a-mediated metabolic-epigenetic axis, providing a promising therapeutic target and a potent candidate agent for the clinical management of DNP.

Keywords:  Carnitine palmitoyltransferase 1a; Diabetic neuropathic pain; Fatty acid oxidation; Phenotypic polarization; Resolvin D2

DOI:  https://doi.org/10.1016/j.neurot.2026.e01111
Neurotherapeutics. 2026 Oct 26. pii: S1878-7479(26)00276-X. [Epub ahead of print]24(1): e01106

Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson's disease via the tim-3/NF-κb axis.

Xi Yin, Miao Wang, Yang Gao, Jiarui Yao, Yifan Li, Tong Chen, Zhenfu Wang, Wei Wang, Zhongbao Gao.

  Microglia-mediated neuroinflammation is a critical driver of dopaminergic neuronal loss in Parkinson's disease (PD), presenting a viable target for disease-modifying therapies. Although the transcription factor Spi-1 proto-oncogene (SPI1) is implicated in microglial regulation, its specific pathological role and therapeutic potential in PD remain elusive. In this study, utilizing in vivo MPTP-induced mouse models and in vitro MPP + stimulated microglia, we identified SPI1 as a crucial regulator of PD-associated neuroinflammation. We found that SPI1 expression is aberrantly upregulated in both PD models. Crucially, SPI1 knockdown significantly mitigated motor deficits, attenuated dopaminergic neuronal loss, and suppressed neuroinflammation by reducing proinflammatory cytokines. Mechanistically, we revealed that SPI1 directly binds to the promoter of T-cell immunoglobulin and mucin-domain-containing 3 (TIM-3) to activate its transcription. Silencing SPI1 facilitated a neuroprotective microglial M1-to-M2 phenotypic shift by downregulating TIM-3 and subsequently inhibiting the NF-κB signaling pathway, thereby protecting against synaptic impairment and neuronal apoptosis. Together, our findings elucidate a novel SPI1/TIM-3/NF-κB regulatory axis in microglial polarization and highlight the targeted inhibition of SPI1 as a promising therapeutic strategy for ameliorating neuroinflammation and halting disease progression in Parkinson's disease.

Keywords:  Neuroinflammation; Neuroprotection; Parkinson’s disease; SPI1/PU.1; TIM-3

DOI:  https://doi.org/10.1016/j.neurot.2026.e01106
Glia. 2027 Jan;pii: e70250. [Epub ahead of print]75(1):

sox17 Mutagenesis Reveals Compounding Effects ofMaternal and Zygotic Contribution on Microglia Abundance.

Camden A Spring, John Dennen, Dailin Gan, Jun Li, Cody J Smith.

Embryonic development is shaped by maternal and zygotic factors but how the interplay between these factors contributes to phenotypic variability and impacts specific populations of brain cells, and subsequently neurodevelopment, remains largely unknown. Here, we reveal a double hit phenomenon that impacts microglia and microglia precursors during development. Using zebrafish, we identified a mutation in sry-related HMG box gene-17 (sox17) that exhibits a maternal effect phenotype presenting as a reduction of microglia in the brain and precursors in the yolk sac. We demonstrate that microglia deficits are exacerbated in homozygous offspring from homozygous parents compared to homozygous offspring from heterozygous parents, suggesting a compounding effect of maternal and zygotic sox17 mutation on microglia abundance. We observe that sox17 is expressed in microglia and yolk sac precursors and is maternally contributed. Injections of sox17 RNA during embryogenesis are sufficient to rescue microglia and yolk sac cell abundance. To identify additional genes interacting with sox17, we perform a genetic screen using CRISPR mutagenesis and identify f11r.1, gas6, and mpp1 as microglia regulators, which we demonstrate are expressed in zebrafish microglia. Transcriptional and mutant analyses with these genes suggest sox17 positively regulates mpp1 transcription. These results demonstrate that microglia are susceptible to additive effects of maternal and zygotic sox17 mutation, and that offspring greatly differ in their susceptibility to microglia deficits depending on the mother's genotype. Our findings highlight that both the maternal and offspring genotype should be considered when examining neurodevelopmental disorders that could arise from microglia dysfunction.

DOI: https://doi.org/10.1002/glia.70250
iScience. 2026 Nov 20. 29(11): 117232

Single-cell transcriptomics reveals reversible microglia/macrophage activation after human retinal neuron transplantation into mouse retina.

Emil Kriukov, Anthony Mukwaya, Paul Francis Cullen, Hio Tong Kam, George Baldwin, Volha V Malechka, Nasrin Refaian, Nikita Bagaev, Everett Labrecque, Sthavir Vinjamuri, Dong Feng Chen, Milica A Margeta, Petr Baranov.

  Host retinal microglia and macrophages can limit donor neuron survival and integration after transplantation, but the cellular mechanisms underlying this response remain unclear. In this study, we used human embryonic stem cell-derived retinal ganglion cells, generated from Brn3b-tdTomato-Thy1.2-derived retinal organoids, and transplanted them subretinally into healthy adult CX3CR1GFP mice. Three days later, GFP-positive host myeloid cells were isolated by fluorescent activated cell sorting and profiled using 10× single-cell RNA sequencing, with immunohistochemistry validating spatial and molecular changes. Transcriptomic and RNA velocity analyses revealed a microglia/macrophage activation continuum, including homeostatic, transitory, proliferative, and activated states. Transplantation induced a disease-associated microglia-like program, marked by reduced Tmem119 and increased Apoe, Lgals3, Spp1, Cybb, and related activation genes. Integrated atlas comparisons linked this response to retinal and neurodegenerative disease-associated myeloid states. Importantly, separate homeostatic-to-activated and activated-to-homeostatic trajectories suggest that transplantation-induced host myeloid activation is dynamic and partially reversible, with implications for improving future retinal cell therapies.

Keywords:  activation; cell fate; inflammation; microglia; retina; single-cell RNA sequencing; transplantation

DOI:  https://doi.org/10.1016/j.isci.2026.117232
Neurochem Res. 2026 Oct 27. pii: 312. [Epub ahead of print]51(6):

β-Glucan Pretreatment Attenuates Single Prolonged Stress-Associated Behavioural and Neuroinflammatory Changes in Male Mice.

Jinxin Li, Minxiu Ye, Xu Lu, Qijun Dai, Chao Huang, Jie Peng.

  Post-traumatic stress disorder (PTSD) is a severe psychiatric disease with limited options for prevention. Neuroinflammation is a key factor in PTSD pathogenesis. Innate immune preconditioning, the prior mild stimulation of microglia, can induce tolerance to PTSD. Because β-glucan is a natural polysaccharide found in fungal cell walls that can stimulate microglia, we investigated whether β-glucan preconditioning can prevent PTSD-like behaviors in the single prolonged stress (SPS) male mouse model. A single intraperitoneal injection of β-glucan (10 and 20, but not 5 mg/kg) one day before SPS significantly prevented SPS-induced increases in contextual and cued fear freezing, as well as anxiety-like behaviors in the elevated plus maze and open field tests. β-glucan (20 mg/kg) administered 1 or 5 days before SPS maintained its protective effects, but this effect was lost at a 10-day interval. Notably, a second injection 10 days after the first and 1 day before SPS, or four daily injections ending 10 days before SPS, also prevented SPS-induced fear- and anxiety-like behaviors. After the final behavioral tests at the end of the SPS model recovery period, β-glucan pretreatment was found to prevent SPS-induced upregulation of tumor necrosis factor-α (Tnf-α), interleukin-1β (Il-1β), and Il-6 mRNA in the brain. Additionally, pharmacological inhibition (minocycline) or depletion (PLX3397) of microglia abolished β-glucan's behavioral and neuroinflammatory protection. These findings demonstrate that β-glucan, likely through stimulation of microglia, prevents PTSD-like behaviors and attenuates neuroinflammatory responses. As β-glucan can be obtained naturally, it may be a potential drug for preventing PTSD-like behaviors, at least in animals.

Keywords:  Innate immune tolerance; Microglia; Neuroinflammation; PTSD; β-glucan

DOI:  https://doi.org/10.1007/s11064-026-04934-0
Viruses. 2026 Sep 25. pii: 1065. [Epub ahead of print]18(10):

A Human iPSC-Derived Tri-Culture Model of NeuroHIV: HIV Infection, Antiretroviral Drug Effects, Microglial Morphology, and Neuronal Calcium Dynamics.

Kara L Gordon, Christine G Rines, Laura-Maria Oja, Steve Gilmore, Lilian Harrison, Alyson Smith, Randall Ingermanson, Vez Repunte-Canonigo, Jefferey H Price, Patrick M McDonough, Pietro Paolo Sanna, Babu L Tekwani.

  HIV-associated neurocognitive disorders (HAND) can persist despite effective ART and are associated with persistent central nervous system (CNS) viral reservoirs in microglia, chronic neuroinflammation, synaptic dysfunction, and neuronal injury. Thus, human-relevant multicellular CNS models are needed to elucidate neuroHIV pathogenesis and ART neurotoxicity. Here, we establish and characterize a fully human induced pluripotent stem cell (hiPSC)-derived CNS tri-culture model comprising isogenic neurons, astrocytes, and microglia that remains viable and functionally active for up to 32 days in vitro. Using a microglia-tropic fluorescent HIV reporter virus, GFP-HIV-AD8, we demonstrate infection of IBA1+ microglia with no detectable infection of IBA1- cells or TUBB3+ neurons. HIV replication was quantified over 14 days post-infection and effectively suppressed by the first-generation integrase strand transfer inhibitor (INSTI)-containing regimen elvitegravir/tenofovir disoproxil fumarate/emtricitabine (EVG/TDF/FTC), and the second-generation INSTI-containing regimens dolutegravir/tenofovir disoproxil fumarate/emtricitabine (DTG/TDF/FTC) and bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC), at concentrations based on reported plasma Cmax values. HIV infection reduced microglial viability by approximately 70%, partially rescued by lower in vitro ART concentrations but worsened by the supratherapeutic 3× Cmax condition of DTG-containing regimens. In uninfected cultures, DTG induced microglial morphological changes consistent with a reactive or dysfunctional state. Calcium imaging revealed ART-specific neuronal effects: EVG/TDF/FTC reduced neuronal activity, whereas BIC/TAF/FTC enhanced it. In HIV-infected cultures, DTG shortened neuronal spike duration under viral suppression, identifying an HIV-DTG-associated electrophysiological phenotype. Overall, BIC/TAF/FTC showed the most favorable profile across the cellular and electrophysiological endpoints assessed in this donor line. Together, these findings establish an hiPSC-derived CNS tri-culture model for controlled studies of neuroHIV virology, ART effects, and neuronal function.

Keywords:  antiretroviral therapy; bictegravir; dolutegravir; iPSC; microglia; morphology; neuroHIV; neuronal calcium; neurotoxicity; tri-culture

DOI:  https://doi.org/10.3390/v18101065
Exp Cell Res. 2026 Oct 28. pii: S0014-4827(26)00311-3. [Epub ahead of print] 115194

Mxd1-mediated transcriptional repression of FTO induces NLRP3-dependent pyroptosis in retinal microglia.

Yi Zhang, Yanting Yang, Xingzhao Xu.

  Pyroptosis of retinal microglial cells represents a key pathological event in degenerative disorders of the retina, yet the molecular drivers of this process remain incompletely understood. This study investigates the molecular drivers of retinal microglial pyroptosis using primary murine retinal microglial cells and HMC3 cells exposed to lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Transmission electron microscopy (TEM) assessed ultrastructural changes, while cell viability, pyroptosis-associated protein markers, and inflammatory cytokine secretion were evaluated via CCK-8, western blotting, and ELISA, respectively. The results showed that LPS/ATP treatment reduced FTO protein levels in both cell types, and enforced FTO expression reversed LPS/ATP-induced pyroptosis. LPS/ATP elevated Mxd1 levels, and Mxd1 protein bound to the FTO promoter to repress its activity. Mechanistically, FTO decreased both m6A abundance and stability of NLRP3 transcripts, thereby lowering NLRP3 expression and suppressing pyroptosis, and this effect required IGF2BP2 as an m6A reader that bound to the coding sequence (CDS) of NLRP3 mRNA to promote its stability. In conclusion, transcriptional repression of FTO driven by Mxd1 facilitates retinal microglial pyroptosis through modulation of NLRP3 in an m6A- and IGF2BP2-dependent manner.

Keywords:  FTO; IGF2BP2; Mxd1; Retina microglia; m6A modifications; pyroptosis

DOI:  https://doi.org/10.1016/j.yexcr.2026.115194