bims-microg 2026-01-18 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–01–18
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Injury-environment interaction: microglial priming by mTBI creates vulnerability to subsequent stress via the HMGB1-RAGE axis.
Integrin-mediated adhesion drives microglial entry into the developing CNS.
Microglial CX3CR1 deficiency regulates the selective vulnerability of cone photoreceptors via STAT3/CCL-ACKR1 signaling in the mouse retina.
Targeting the CCL7-STAT1 axis attenuates microglial neurotoxicity and photoreceptor degeneration in retinitis pigmentosa.
IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.
Prenatal glucocorticoids exposure disrupts maturation of a cluster of microglia, causing poor social memory and more repetitive behaviors.
NLRP3/GSDMD-dependent neutrophil extracellular traps exacerbate microglia-mediated neuroinflammation following traumatic brain injury.
Molecular mechanisms of environmental bisphenol exposure in major depressive disorder: A multimodal analysis.
A novel Mediterranean diet-inspired supplement reduces hippocampal amyloid deposits and microglial activation through the modulation of the microbiota gut-brain axis in 5xFAD mice.
Targeting microglial inflammation in Parkinson's disease: irisin activates PAFAH1B1-RAGE ubiquitination and TFEB-dependent autophagy to alleviate neurodegeneration.
Retinal Amyloid Clearance Enhanced by 40-Hz Light Flicker via MHC-II+ Microglia Regulation in Mice.
Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.
PLGA Nanoparticles Restore Acidic pH and Degradative Function to Compromised Lysosomes with Cy3-Labeling Providing Enhanced Tracking to Lysosomes.
A Daily Injection Paradigm Disrupts the Environmental-Enrichment-Induced Pruning of Miswired Axonal Projections in Developing Mice.
Role of CTRP9 in obesity-associated microglial dysregulation: Promoting lipophagy via the PI3K/AKT/FOXO1 signaling pathway.
Microglial dynamics and ferroptosis induction in human iPSC-derived neuron-astrocyte-microglia tri-cultures.
Sp1-Mettl14 Feedback Loop Promotes Ferroptosis in Mycobacterium tuberculosis-Infected Microglia by Activating Acsl4.
Mechanistic Study of S100A8-mediated Ferroptosis in Vascular Dementia Through the JAK2/STAT3 Pathway.
Paclitaxel induces trained immunity via the GPR183-STING axis to enhance host defense against MRSA infection.

Brain Behav Immun. 2026 Jan 08. pii: S0889-1591(26)00021-8. [Epub ahead of print] 106273

Injury-environment interaction: microglial priming by mTBI creates vulnerability to subsequent stress via the HMGB1-RAGE axis.

Jing Qiu, Guang Yang, Jingling Cai, Chen Chen, Shiting Liang, Haohao Huang, Lianting Ma.

   BACKGROUND: The mechanisms underlying the increased risk of depression following mild traumatic brain injury (mTBI) remain poorly understood, particularly the synergistic interaction between the initial injury and subsequent environmental stress. This study aims to elucidate the molecular cascade governing this "injury-stress" synergy.
METHODS: We developed a "two-hit" mouse model combining mTBI with chronic unpredictable mild stress (CUMS) to investigate their interaction. Our approach integrated behavioral testing with molecular, immunohistochemical, and targeted genetic manipulations (AAV-mediated) in the medial prefrontal cortex (mPFC) to establish causal links.
RESULTS: We found that mTBI alone did not induce significant behavioral deficits but instead established a state of latent vulnerability by driving persistent microglial priming in the mPFC. Sustained release of High-Mobility Group Box 1 (HMGB1) post-mTBI was identified as the key driver of this priming. Mechanistically, we demonstrate that chronic stress did not act by further increasing HMGB1 levels, but by amplifying downstream signaling efficiency through the selective upregulation of its receptor, RAGE. Bidirectional genetic interventions confirmed that RAGE is the critical molecular switch that translates the "second-hit" of stress into pathological amplification, culminating in exacerbated neuroinflammation, synaptic loss, and severe behavioral deficits.
CONCLUSION: Our study untangles a "priming-triggering" mechanism of injury-environment interaction, identifying the HMGB1-RAGE axis as its key molecular mediator. This finding not only enhances our understanding of how latent vulnerability transitions into overt neuropsychiatric disease, but also provides a promising target for preventive intervention.

Keywords:  Chronic stress; Depression; HMGB1-RAGE axis; Microglia priming; Mild traumatic brain injury; Neuroinflammation; Second-hit

DOI:  https://doi.org/10.1016/j.bbi.2026.106273
Dev Cell. 2026 Jan 14. pii: S1534-5807(25)00767-1. [Epub ahead of print]61(1): 7-8

Integrin-mediated adhesion drives microglial entry into the developing CNS.

Fanny Jaudon, Lorenzo A Cingolani.

In this issue of Developmental Cell, Petry et al. show that early microglial progenitors infiltrate the embryonic CNS via an extracellular matrix (ECM)-rich pial route requiring talin-1-dependent integrin activation. This work revises long-standing vascular entry models and highlights mechanosensitive adhesion as a regulator of early neuroimmune assembly.

DOI: https://doi.org/10.1016/j.devcel.2025.12.006
Exp Mol Med. 2026 Jan 15.

Microglial CX3CR1 deficiency regulates the selective vulnerability of cone photoreceptors via STAT3/CCL-ACKR1 signaling in the mouse retina.

Rong Li, Jing Zhang, Qiong Wang, Jun-Qi Fan, Bin Lin.

Selective neuronal vulnerability is a common feature of neurodegenerative disorders. However, the molecular mechanisms that drive this selective vulnerability are not fully understood. Here we observed that microglial CX3CR1 interference induced proinflammatory responses in microglia and astrocytes that were correlated with the selective vulnerability of cone photoreceptors in the mouse retina. Via proteomic analysis, we identified STAT3 as a potential downstream target by which CX3CR1 mediates microglial neurotoxicity. Moreover, single-cell RNA sequencing analysis revealed that CX3CR1-deficient microglia exhibit eight distinct transcriptomic phenotypes. At the mechanistic level, our data revealed that the involvement of Tnf-dominant microglia occurred mainly via microglia‒cone interactions through CCLs and their receptor, atypical chemokine receptor 1 (Ackr1), whose expression was upregulated primarily in cones through NF-κB signaling, leading to selective cone loss. In addition, we found that Cxcl1-dominant microglia primarily communicated with astrocytes via the Bmp2-Bmpr1a/Bmpr1b pair, leading to increased STAT3 levels and, consequently, elevated CCL and CXCL production in astrocytes, which in turn contributed to further cone loss through Ackr1. Overall, our data demonstrate that microglial CX3CR1 deficiency induces selective cone cell death via activation of the STAT3/CCL-ACKR1 signaling pathway, and that targeting CX3CR1/STAT3 could represent a therapeutic strategy to reduce microglial neurotoxicity.

DOI: https://doi.org/10.1038/s12276-025-01618-7
J Neuroinflammation. 2026 Jan 16.

Targeting the CCL7-STAT1 axis attenuates microglial neurotoxicity and photoreceptor degeneration in retinitis pigmentosa.

Rong Li, Jing Zhang, Jun-Qi Fan, Bin Lin.

  Retinitis pigmentosa (RP), the most prevalent inherited retinal degenerative disorder, manifests as progressive and irreversible photoreceptor loss with no approved disease-modifying therapies. Emerging evidence implicates microglia-mediated neuroinflammation as a critical accelerator of RP progression, but its underlying molecular mechanisms remain elusive. Through single-cell RNA sequencing (scRNA-seq) of retinal microglia from the rd10 mouse model of RP, we identified Ccl7 as an important driver of microglial inflammation and defined a distinct subpopulation of CCL7hi microglia as pivotal orchestrators of neuroinflammation and photoreceptor degeneration. Evidently, genetic knockdown of Ccl7 suppressed microglial activation and neuroinflammation, attenuated photoreceptor degeneration, and preserved visual function in rd10 mice, while exogenous CCL7 administration exacerbated microglial reactivity and accelerated photoreceptor apoptosis. Ccl7 upregulation in microglia induced a characteristic senescent signature and promoted pathological phagocytosis, contributing to inflammation and photoreceptor cell death. Mechanistically, microglial Ccl7 trigger a self-amplifying inflammatory cascade by activating STAT1 signaling, and propagate inflammation cascades through CCL7-CCR1/5 inter-microglial communication. Our results establish the CCL7-STAT1 axis as an important regulator of microglial dysfunction in RP. Targeting this pathway represents a promising disease-modifying strategy to halt RP progression, with significant implications for clinical translation.

Keywords:  CCL7; CCR1/5; Microglia; Neuroinflammation; Photoreceptor degeneration; Retina; Retinitis pigmentosa; STAT1

DOI:  https://doi.org/10.1186/s12974-026-03692-8
J Neuroinflammation. 2026 Jan 13.

IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.

Yixuan Du, Lingxi Wu, Yang Mao, Song Chen, Xiangdong Gao.



Keywords:  Alzheimer's disease; Astrocyte-microglial communication; IL-27; Oral GLP-1RA; cGAS lactylation

DOI:  https://doi.org/10.1186/s12974-025-03683-1
Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01592-X. [Epub ahead of print]45(1): 116820

Prenatal glucocorticoids exposure disrupts maturation of a cluster of microglia, causing poor social memory and more repetitive behaviors.

Baixiu Zheng, Ning Zhang, Meng Hu, Yao Zhou, Ziyi Zhang, Yi You, Chenyu Xiao, Qikun Zhao, Shuhuan Feng, Xinrong Wang, Yiting Ping, Xinlei Mo, Jiahui Chen, Yujia Wang, Xiaohui Liu, Yanrong Zheng, Cenglin Xu, Hou-Wen Lin, Hui Wang, Weiwei Hu, Zhong Chen.

  Prenatal glucocorticoid exposure is associated with higher risks of autism spectrum disorder (ASD), yet the underlying mechanisms remain poorly understood. Here, we report that late-pregnancy exposure to dexamethasone (a synthetic glucocorticoid) induces social memory deficiency and increased repetitive behaviors in offspring with an imbalance of neurotransmission in the hippocampus. Single-cell RNA sequencing uncovers an expansion of MRC1+ microglia, with arrested maturation. Strikingly, this population exhibits selective F13a1 (encoding a coagulation factor functioning as transglutaminase) upregulation. Early postnatal inhibition of F13A1 restores microglial maturation and ameliorates behavioral abnormalities. An elevated level of F13A1 is also observed in the plasma of postnatal rats and human umbilical cord blood exposed to prenatal glucocorticoids. Together, it suggests that prenatal glucocorticoid exposure disrupts the maturation of MRC1+ microglia, thereby causing social memory impairment and increased repetitive behaviors. This underscores that arrested maturation within a cluster of microglia may be related to ASD and identifies F13A1 as a promising therapeutic target and biomarker.

Keywords:  CP: Immunology; CP: Neuroscience; F13a1; border-associated macrophages; microglia; prenatal glucocorticoids exposure; repetitive behaviors; social memory deficiency

DOI:  https://doi.org/10.1016/j.celrep.2025.116820
Cell Commun Signal. 2026 Jan 12.

NLRP3/GSDMD-dependent neutrophil extracellular traps exacerbate microglia-mediated neuroinflammation following traumatic brain injury.

Liang Liu, Bingyou Yuan, Yuhua Wang, Jianpeng Liu, Peiyu Li, Haifeng Zhang, Xian Zhang, Jianhao Wang, Yan Chai, Quanjun Deng, Jianning Zhang, Xin Chen.

  Traumatic brain injury (TBI) induces profound neuroinflammation, leading to secondary brain damage and neurological dysfunction. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in amplifying inflammatory responses after injury. This study investigates the involvement of the NLRP3 inflammasome and gasdermin D (GSDMD) in regulating NET formation and subsequent microglia-mediated neuroinflammation after TBI. Using a male mouse model of TBI, we demonstrate that activation of the NLRP3/GSDMD axis significantly enhances NET release from neutrophils. These NETs further activate microglia, promoting the secretion of proinflammatory cytokines, exacerbating blood-brain barrier damage, and worsening neurological deficits. Pharmacological inhibition of NLRP3 and GSDMD markedly attenuates NET formation, reduces microglial activation, and ameliorates neuroinflammation and neurological deficits. Collectively, our findings reveal a mechanistic pathway linking NLRP3/GSDMD-dependent NET formation with microglia-driven neuroinflammation, providing potential therapeutic targets for mitigating secondary injury following TBI.

Keywords:  Blood–brain barrier; GSDMD; Microglia; NETs; NLRP3; Neuroinflammation; TBI

DOI:  https://doi.org/10.1186/s12964-025-02641-x
Ecotoxicol Environ Saf. 2026 Jan 12. pii: S0147-6513(26)00045-X. [Epub ahead of print]309 119716

Molecular mechanisms of environmental bisphenol exposure in major depressive disorder: A multimodal analysis.

Jianlin Li, Junyu Chen, Ying Luo, Yi Li, Xiao Cheng, Yang Xie.

  Bisphenol compounds are pervasive environmental contaminants linked to neuropsychiatric disorders, yet their molecular interactions with major depressive disorder (MDD) pathogenesis remain unclear. This study employed an integrative approach combining network toxicology, machine learning, single-cell analysis, molecular docking, molecular dynamics simulations, and animal experiments to systematically identify key targets and pathways through which bisphenols may contribute to MDD. Network analysis of 123 shared targets between bisphenols and MDD revealed enrichment in corticosteroid responses, nuclear receptor activity, and oxidative stress pathways. Machine learning analysis prioritized five high-confidence biomarkers: PTGS1, MMP8, MAPK14, DAO, and BCHE, all of which exhibited significant differential expression in MDD patients (p < 0.05). Single-cell RNA sequencing revealed cell-type-resolved expression patterns, with BCHE enriched in oligodendrocyte precursor cells and reduced in MDD, while MAPK14 was broadly expressed across neuronal and glial populations, and PTGS1 showed relatively higher signal in microglia. Molecular docking suggests that the bisphenol compound exhibits stable binding affinities toward these five targets. Molecular docking and molecular dynamics simulations demonstrated strong binding affinities between bisphenols and DAO/BCHE, with stability confirmed over a 100 ns simulation. Animal experiments supported these findings, showing that bisphenol-exposed mice exhibited exacerbated depressive-like behavioural phenotypes. Consistently, qPCR and Western blot analyses of mouse brain tissue homogenates revealed that DAO expression was significantly downregulated, whereas PTGS1, MMP8, MAPK14, and BCHE were significantly upregulated, consistent with computational predictions. These findings provide a novel molecular framework for understanding the link between environmental pollutants and mental disorders, confirming the neurotoxic effects of bisphenol compounds.

Keywords:  Bisphenol compounds; Machine learning algorithms; Major depressive disorder; Molecular docking; Molecular dynamics simulations; Network toxicology

DOI:  https://doi.org/10.1016/j.ecoenv.2026.119716
Gut Microbes. 2026 Dec 31. 18(1): 2614030

A novel Mediterranean diet-inspired supplement reduces hippocampal amyloid deposits and microglial activation through the modulation of the microbiota gut-brain axis in 5xFAD mice.

Emily Connell, Gwénaëlle Le Gall, Simon McArthur, Leonie Lang, Bernadette Breeze, Marrium Liaquat, Matthew G Pontifex, Saber Sami, Line Pourtau, David Gaudout, Michael Müller, David Vauzour.

   BACKGROUND: Alzheimer's disease (AD) is projected to increase in prevalence, heightening the need for strategies to alleviate its neuropathological burden. The bioactive constituents of a Mediterranean-style diet are well-recognised for their neuroprotective properties. Due to their capacity to alter the gut microbiome composition, these benefits may involve modulation of the microbiota-gut-brain axis. In this study, we investigated whether a novel supplement enriched with key Mediterranean diet-derived bioactives (Neurosyn240) could reduce amyloid deposition and microglial activation in 5xFAD mice, a transgenic model of AD, through microbiota-mediated mechanisms.
METHODS: Male and female 5xFAD transgenic mice (n = 16 per sex) were randomly assigned to receive either a standard control diet or a diet supplemented with Neurosyn240 for 12 weeks. Employing a multi-omics approach, gut microbiota composition was profiled using 16S rRNA ampliconsequencing, serum metabolites were quantified via targeted metabolomics, and hippocampal gene expression was analysed through qPCR and RNA sequencing. Neuropathological markers, including amyloid-β deposition and microglial activation, were evaluated using immunofluorescence staining. Statistical analyses were performed using two-way ANOVA to examine the main effects of diet and sex and their interaction.
RESULTS: Neurosyn240 significantly shifted the gut microbiome composition, which was associated with increased circulatory serotonin levels and decreased kynurenine and bile acids (TCA, HDCA, TDCA, CDCA and LCA) concentrations. In the brain, Neurosyn240 consumption led to a significant reduction in hippocampal amyloid deposits and Iba-1 positive microglia (p<0.05), which were associated with decreased LCA and increased serotonin, respectively. Hippocampal RNA sequencing further highlighted the upregulation of genes involved in promoting amyloid beta clearance mechanisms.
CONCLUSIONS: Together, these findings highlight novel neuroprotective effects of Neurosyn240 in modulating metabolite-mediated pathways of the microbiota-gut-brain axis, accentuating its therapeutic potential against AD progression.

Keywords:  Mediterranean diet; amyloid deposits; brain; gut microbiome; hippocampus; microbial-derived metabolites; microglia

DOI:  https://doi.org/10.1080/19490976.2026.2614030
Commun Biol. 2026 Jan 10.

Targeting microglial inflammation in Parkinson's disease: irisin activates PAFAH1B1-RAGE ubiquitination and TFEB-dependent autophagy to alleviate neurodegeneration.

Lijun Cai, Yin Liu, Shuang Tang, Song Deng, Li Zhang, Yiping Wang, Bei Zhang, Bing Han, Rujia Xie, Xin Liao, Qin Yang.

Investigate irisin's therapeutic potential in Parkinson's disease (PD). Clinical data from 120 PD patients and 120 controls were analyzed. MPTP-induced PD mice and LPS-stimulated BV2 microglia models were used. In vivo, mice were divided into control, PD, and PD + Irisin groups for behavioral and histological assessments. In vitro, LPS-stimulated BV2 cells were treated with irisin or PBS. RNA sequencing, immunohistochemistry, and Western blot evaluated autophagy, inflammation, and ubiquitination pathways. PD patients exhibited increased TNF-α and IL-1β but decreased irisin levels. In PD mouse models, irisin improved motor deficits, increased nigrostriatal neuron numbers, restored tyrosine hydroxylase expression, and reduced α-synuclein aggregation. It also suppressed microglial inflammation and promoted anti-inflammatory polarization. Mechanistically, irisin enhanced autophagic flux, regulated RAGE ubiquitination mediated by PAFAH1B1, and inhibited neuroinflammation via the TFEB-NLRP3 axis. Specifically, PAFAH1B1 regulated RAGE expression through K61 and K169 sites on K48-linked polyubiquitin chains. Additionally, irisin restored lysosomal function by promoting TFEB nuclear translocation, enhancing NLRP3 inflammasome degradation, and reducing inflammatory factor secretion, thus alleviating neuroinflammation. Irisin alleviates PD pathology by modulating autophagy and ubiquitination pathways, suggesting its potential as a novel immunomodulatory target for PD.

DOI: https://doi.org/10.1038/s42003-025-09389-7
Invest Ophthalmol Vis Sci. 2026 Jan 05. 67(1): 32

Retinal Amyloid Clearance Enhanced by 40-Hz Light Flicker via MHC-II+ Microglia Regulation in Mice.

Wang Sheng, Qichang Wang, Yinhua Huang, Jianing Gu, Chengcheng Ding, Zekai Cui, Shibo Tang, Xiaobo Xia, Jiansu Chen.

Purpose: This study aimed to investigate whether 40-Hz light flicker could modulate the expression of major histocompatibility complex class II (MHC-II) and enhance the clearance of amyloid-β (Aβ) deposition.
Methods: We examined retinal MHC-II expression via RNA sequencing, immunofluorescence, and western blotting in mice 8 weeks, 9 months, and 18 to 20 months old. Retinal metabolic waste accumulation was induced by intravitreal and subretinal injections of Aβ oligomers. The impact of 40-Hz flicker on MHC-II expression, microglial activation, and retinal function was evaluated using immunofluorescence, western blotting, dot immunobinding assay, electroretinography, and optokinetic reflex (OKR) testing. Minocycline was used to inhibit microglial activity.
Results: The 40-Hz light flicker upregulated MHC-II expression in the retinas of aged mice. MHC-II⁺ microglia accumulated along retinal veins and exhibited increased numbers and enlarged morphology in the subretinal space. Following intravitreal or subretinal Aβ injection, 40-Hz flicker enhanced microglial activation, further upregulated MHC-II expression, promoted Aβ clearance, and improved electroretinogram responses and OKR performance. These effects were abolished by minocycline treatment.
Conclusions: We observed that 40-Hz light flicker enhances retinal microglial clearance of Aβ oligomers by upregulating MHC-II expression. These findings support 40-Hz light flicker as a non-invasive therapeutic strategy for age-related retinal disorders by promoting metabolic waste clearance.

DOI: https://doi.org/10.1167/iovs.67.1.32
Invest Ophthalmol Vis Sci. 2026 Jan 05. 67(1): 4

Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.

Hiroto Yasuda, Shinsuke Nakamura, Aimi Shirakawa, Yoshiki Kuse, Masamitsu Shimazawa.

Purpose: Mitochondria are highly dynamic organelles that continuously undergo fission and fusion, and their dysfunction is associated with various age-related disorders. This study aimed to elucidate the role of mitochondrial fission in the development of choroidal neovascularization (CNV), a hallmark of neovascular age-related macular degeneration (AMD), and to evaluate the therapeutic potential of its pharmacological inhibition.
Methods: The murine CNV model was created by laser photocoagulation using C57BL/6J mice. Expression changes of mitochondrial fission-related protein during CNV development were examined using western blotting and immunofluorescence. To assess the effectiveness of pharmacological inhibition of mitochondrial fission, the effects of mitochondrial division inhibitor-1 (Mdivi-1) and mitochondrial fusion promoter (M1) were evaluated by CNV area measurement, fluorescein angiography, and western blot analysis. The pro-angiogenic mechanisms associated with mitochondrial fission were further investigated in RPE cells cultured under hypoxic condition.
Results: In a murine laser-induced CNV model, mitochondrial fission-related proteins increased in the retinal pigment epithelium (RPE)-choroid complex, and the high expression of phosphorylated dynamin-related protein 1 (DRP1) was observed in RPE cells surrounding the CNV lesion. Additionally, intravitreal injection of Mdivi-1 or M1 suppressed CNV formation, vascular leakage, and pro-angiogenic factor production. In RPE cells exposed to hypoxia, DRP1-mediated mitochondrial fission was rapidly activated, accompanied by increased mitochondrial reactive oxygen species production. Moreover, inhibition of mitochondrial fission suppressed mitochondrial bioenergetic dysfunction and the upregulation of vascular endothelial growth factor.
Conclusions: These findings support that pharmacological inhibition of activated mitochondrial fission could serve as a potential therapeutic approach for neovascular AMD.

DOI: https://doi.org/10.1167/iovs.67.1.4
Am J Physiol Cell Physiol. 2026 Jan 14.

PLGA Nanoparticles Restore Acidic pH and Degradative Function to Compromised Lysosomes with Cy3-Labeling Providing Enhanced Tracking to Lysosomes.

Jiaqi Li, Tianchen Wang, Wennan Lu, Davit Jishkariani, Andrew Tsourkas, Simon Kaja, Kyle H Vining, Jedtanut Thussananutiyakul, Ashley Spence, Rohini M Nair, Joshua L Dunaief, Claire H Mitchell.

  Lysosomal dysfunction and elevated lysosomal pH are hallmark features of age-related neurodegenerative diseases including Age-related Macular Degeneration (AMD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). Restoring lysosomal acidity is important for maintaining enzymatic degradation, preventing protein aggregation, and reducing cellular waste accumulation in degenerating tissues. Acidic nanoparticles represent a promising therapeutic strategy to normalize lysosomal pH; however, accurate monitoring of their delivery, retention, and dosage is critical for rigorous evaluation. To address this, we developed fluorescently labeled poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles conjugated with Cyanine3 amine (Cy3). Nanoparticle uptake was systematically optimized, achieving over 90% delivery to lysosomes of induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake rates varied among adjacent cells. Once internalized, nanoparticles demonstrated remarkable stability, with no detectable change in concentration, distribution, or size for at least 28 days. iPS-RPE cells exhibited higher nanoparticle internalization compared to the ARPE-19 cell line and optic nerve head astrocytes. The capacity of the nanoparticles to restore function to stressed lysosomes was confirmed by their ability to reacidify lysosomes, restore cathepsin B activity and increase levels of active cathepsin D. The nanoparticles also reduced levels of LC3II in astrocytes treated with chloroquine, indicating they can also restore autophagy rates. In summary, this study demonstrates the value of Cy3 labeling for enhanced nanoparticle tracking to lysosomes. The findings also identify PLGA nanoparticles as powerful tools for restoring degradative lysosomal function and autophagy in cells undergoing lysosomal stress.

Keywords:  Lysosomal pH; age dependent neurodegenerations; autophagy; nanoparticle trafficking; retina

DOI:  https://doi.org/10.1152/ajpcell.00494.2025
Dev Neurobiol. 2026 Jan;86(1): e70003

A Daily Injection Paradigm Disrupts the Environmental-Enrichment-Induced Pruning of Miswired Axonal Projections in Developing Mice.

Lara Rogerson-Wood, Atomu Sawatari, Claire S Goldsbury, Catherine A Leamey.

  The capacity for enhanced experience, modeled as environmental enrichment (EE) in laboratory animals, to drive positive changes in brain circuitry presents a promising avenue in the development of therapies for neurodevelopmental conditions. Less understood are the underlying mechanisms, or potential interactions of EE with other therapeutic approaches. We have previously shown that early exposure to EE can drive the partial repair of miswired uncrossed retinal projections, and the concomitant rescue of a visual behavior, in the Ten-m3 knockout (KO) mouse. This was associated with a highly spatiotemporally localized upregulation of microglial reactivity in the region where the correction was occurring which peaked around postnatal day (P)25. Aiming to confirm a causal role for microglial-mediated engulfment in this process, we assessed the effect of daily injections of minocycline or vehicle saline from P18 to P24 (inclusive) on measures of microglial reactivity and anatomical corrective pruning in P25 Ten-m3 KO mice. While an effect of EE was confirmed at this timepoint, intriguingly, we found that both the vehicle- and minocycline-treated mice had a similar lack of microglial reactivity and showed a marked absence of corrective pruning of their miswired retinal projections. This suggests that the injection procedure itself disrupted the experience-induced microglial-mediated circuit repair. These results underscore the highly sensitive nature of EE-driven corrective pruning actions of microglia and the critical importance of considering and controlling for all aspects of experience.

Keywords:  development; environmental enrichment; injection; microglia; stress; synaptic pruning; vehicle

DOI:  https://doi.org/10.1002/dneu.70003
Cell Signal. 2026 Jan 10. pii: S0898-6568(26)00007-0. [Epub ahead of print]140 112358

Role of CTRP9 in obesity-associated microglial dysregulation: Promoting lipophagy via the PI3K/AKT/FOXO1 signaling pathway.

Peng-Quan Chen, Ya-Dong Wei, Xin Zheng, Quan-Tong Xu, Song-Lin Xu, Shuai He, Meng-Jie Xu, Jin-Fang Ge.

  Activation of microglia triggers neuroinflammation, which subsequently leads to neurological dysfunction, representing a significant pathological mechanism underlying obesity-related cognitive impairment. Microglial lipophagy plays a critical role in regulating lipid homeostasis and inflammation; however, its involvement in obesity-related cognitive impairment remains largely unexplored. The accumulation of lipid droplets in microglia is a prominent feature of aging and reflects an imbalance in microglial lipid metabolism. CTRP9 is an important regulator in this process. The aim of this study was to investigate the potential role of CTRP9 in high-fat diet-induced disruption of microglial lipid metabolism. First, cognitive impairment was observed in an obesity model induced by a high-fat diet. We then observed a significant increase in lipid droplets in hippocampal microglia, inhibition of autophagic activity, and decreased CTRP9 expression in obese mice with cognitive impairment. Additionally, both BV2 and HMC3 cells stimulated with palmitic acid (PA) displayed lipid droplet accumulation, along with impaired lipophagy. Mechanistically, PA stimulation significantly reduced CTRP9 expression. To further investigate the role of CTRP9, we demonstrated that silencing CTRP9 exacerbated lipophagy impairment and increased lipid droplet accumulation in microglia. Conversely, overexpression of CTRP9 was able to reverse the aberrant activation of the PI3K/AKT/FOXO1 signaling pathway in PA-stimulated BV2 cells, thereby ameliorating these phenotypes. Taken together, these results suggest that CTRP9 plays a crucial regulatory role in lipid metabolism disorders in high-fat-stimulated microglia, and its mechanism may be closely linked to the dysfunction of the PI3K/AKT/FOXO1 signaling pathway.

Keywords:  CTRP9; Lipophagy; Microglia; Obesity

DOI:  https://doi.org/10.1016/j.cellsig.2026.112358
FEBS Open Bio. 2026 Jan 14.

Microglial dynamics and ferroptosis induction in human iPSC-derived neuron-astrocyte-microglia tri-cultures.

Hongmei Lisa Li, Hiroko Ohmiya, Sou Sakamoto, Masato Yugami, Akiko Oki, Makoto Furusawa, Yan Ling.

  The dynamics of microglial activity within neuron-astrocyte-microglia tri-cultures derived from human induced pluripotent stem cells (iPSCs) present a complex interplay and offer an opportunity to obtain new insights into neuron-glia interactions. Iron-laden microglia, correlating with functional changes, represent a key pathological feature of Alzheimer's disease (AD). This study characterized the cellular crosstalk and transcriptional states of microglia in tri-cultures. Complement C3 can be detected in culture media when microglia are cocultured with neurons, and the addition of astrocytes in the coculture led to an increased amount of C3, indicating that the impact of glial interactions can be evaluated in this model system. We compared microglial gene expression profiles comprehensively in monoculture, coculture, and tri-culture settings. Single-cell RNA sequencing (scRNA-seq) revealed various microglial states with gene expression changes associated with endocytosis and neuron-related functions in tri-culture settings, suggesting that microglial behavior is profoundly impacted by the presence of neurons and astrocytes. We assessed microglial responses to iron overload combined with the ferroptosis inducer RSL3 (a GPX4 inhibitor) in tri-cultures. Microglial cell death was accompanied by ferritin heavy-chain expression, indicating microglia ferroptosis. scRNA-seq analyses highlighted alterations in pathways related to ferroptosis, stress response, and autophagy, indicating substantial shifts in microglial profiles upon iron perturbation. These findings underscore the necessity of using tri-cultures as a model to capture certain degrees of complex cellular interactions occurring in vivo. These results offer critical insights for establishing in vitro models for therapeutic development of neurodegenerative diseases, including AD.

Keywords:  ferroptosis; iPSC tri‐culture; single‐cell RNA‐seq; transcriptomics

DOI:  https://doi.org/10.1002/2211-5463.70182
Basic Clin Pharmacol Toxicol. 2026 Feb;138(2): e70183

Sp1-Mettl14 Feedback Loop Promotes Ferroptosis in Mycobacterium tuberculosis-Infected Microglia by Activating Acsl4.

Junhao Chu, Quansheng Liu, Xue Chen, Aili Jia, Xing Chen.

  Central nervous system tuberculosis (CNS-TB) represents a critical form of extrapulmonary tuberculosis, characterized by high mortality and morbidity. The infection of microglia by Mycobacterium tuberculosis (Mtb) is a crucial factor in the progression of CNS-TB. Ferroptosis plays a significant role in various neurological disorders. However, it remains unclear whether Mtb can induce ferroptosis in microglia and what mechanisms underlie this process. This study demonstrated that Mtb H37Rv infection can induce ferroptosis in microglia, which is characterized by the accumulation of ferrous ions, increased levels of lipid ROS, depletion of glutathione, enhanced lipid peroxidation and reduced expression of Slc7a11 and Gpx4. Additionally, Mtb infection upregulated Sp1 expression, and Sp1 knockdown led to a suppression of ferroptosis induced by Mtb. Mechanistically, we found that Sp1 enhanced the transcription of Mettl14. Subsequently, the N6-methyladenosine modification mediated by Mettl14 stabilized the mRNA of Acsl4, ultimately inducing ferroptosis. Mettl14 also was found to enhance the stability of Sp1 mRNA, establishing a positive regulatory feedback loop. Moreover, knockdown of Acsl4 attenuated Sp1- or Mettl14-mediated ferroptosis in Mtb-infected microglia. Overall, our findings establish a connection between Mtb infection and ferroptosis and delineate a novel mechanism through which H37Rv induces ferroptosis in microglia via the Sp1-Mettl14-Acsl4 axis, offering new insights into the pathogenesis of CNS-TB.

Keywords:  N6‐methyladenosine; central nervous system tuberculosis; ferroptosis; microglia

DOI:  https://doi.org/10.1111/bcpt.70183
Appl Biochem Biotechnol. 2026 Jan 15.

Mechanistic Study of S100A8-mediated Ferroptosis in Vascular Dementia Through the JAK2/STAT3 Pathway.

XiaoYu Liu, XiuMin Zhao, BaiKe Zhu, YanHong Yu, MeiLing Sun, HaiLing Lv, Jun Zhang, AiJu Liu.

   OBJECTIVE: To explore the mechanism of S100 Calcium Binding Protein A8 (S100A8)-mediated ferroptosis in vascular dementia (VaD) via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway.
METHODS: To establish models of VaD and study microglial responses, we employed bilateral carotid artery stenosis (BCAS) in mice and oxygen-glucose deprivation (OGD) in BV2 cells, respectively. The cognitive function of mice was assessed by Morris water maze experiments. The pathological changes of brain tissue were observed by Nissl staining and luxol fast blue staining. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay. The co-localization of S100A8 was identified by immunofluorescence. Ferroptosis was assessed by related indices such as intracellular Fe2+ content, reactive oxygen species, mitochondrial membrane potential and lipid peroxidation. JAK2/STAT3 pathway activation was evaluated by Western blot.
RESULTS: In BCAS mice, cerebral hypoperfusion triggered the upregulation of S100A8 in hippocampal microglia. This upregulation showed a progressive increase following surgery, peaking at 28 days post-BCAS. Inhibition of S100A8 improved cognitive deficits, attenuated brain damage, reduced neuroinflammation, and suppressed ferroptosis in BCAS mice. In BV2 cells, S100A8 silencing alleviated inflammation and ferroptosis induced by OGD. The anti-inflammatory effects of S100A8 silencing were counteracted by Erastin but amplified by Ferrostatin-1‌. Furthermore, S100A8 inhibition blocked JAK2/STAT3 activation; however, the JAK2/STAT3 agonist Colivelin TFA reversed the protective effects of S100A8 silencing in OGD-treated BV2 cells.
CONCLUSION: S100A8 mediates ferroptosis in VaD via JAK2/STAT3 pathway.

Keywords:  Chronic cerebral hypoperfusion; Ferroptosis; JAK2/STAT3; S100A8; Vascular dementia

DOI:  https://doi.org/10.1007/s12010-025-05527-3
Vet Res. 2026 Jan 16.

Paclitaxel induces trained immunity via the GPR183-STING axis to enhance host defense against MRSA infection.

Cheng-Kai Zhou, Jia-Bao Zhang, Yong-Jun Yang, Wei Chen, Zhen-Zhen Liu.

  Methicillin-resistant Staphylococcus aureus (MRSA) remains a major global health threat with limited prophylactic options. Trained immunity, characterized by nonspecific functional reprogramming of innate immune cells, offers a promising strategy for infection control. Here, we identify paclitaxel (PTX), a microtubule-stabilizing agent widely used in cancer therapy, as a novel inducer of trained immunity in macrophages. Unlike the microtubule-destabilizing agent nocodazole (Noco), PTX enhanced macrophage proinflammatory responses, phagocytosis, and bacterial killing upon secondary stimulation. Mechanistically, PTX-induced training activated the stimulator of interferon genes protein (STING) pathway, evidenced by increased phosphorylation of STING, TBK1, and IRF3. STING deficiency abolished the trained immune responses and antimicrobial functions. PTX also triggered metabolic reprogramming toward aerobic glycolysis via the Akt-mTOR-HIF1α pathway, which was essential for the trained phenotype. Transcriptomic and functional analyses further revealed that the GPR183-STING axis mediated PTX-induced trained immunity. Inhibition of GPR183 impaired STING activation and suppressed functional responses in vitro. In a murine MRSA pneumonia model, PTX-trained mice showed reduced bacterial burden, preserved lung barrier integrity, and enhanced immune activation, all of which were reversed by GPR183 inhibition or STING deficiency. Collectively, our findings uncover a previously unrecognized immunomodulatory function of PTX and highlight the therapeutic potential of targeting the GPR183-STING axis to enhance trained immunity against resistant bacterial infections.

Keywords:  MRSA; Paclitaxel; infection prevention; macrophages; trained immunity

DOI:  https://doi.org/10.1186/s13567-025-01704-8