bims-microg 2025-11-09 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–11–09
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Lymphoid gene expression supports neuroprotective microglia function.
Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.
Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.
Microglia alter sex-specific cerebellar myelination following placental hormone loss.
G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.
Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice.
Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder.
Targeting lysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing.
Ferroptosis-inducing effects of cromolyn in microglia through NCOA4-mediated ferritinophagy.
Fatty acid-binding protein 4 drives microglia-mediated neuroinflammation through promoting S100A9 expression and lipid droplet accumulation after intracerebral hemorrhage.
Inflammation associated microglial expansion disrupts hippocampal glial network communication, driving postoperative neurocognitive impairment.
Targeting hypercoagulability in ischemic stroke modulates fibrin-driven microglial polarization via JAK-STAT pathway.
ATF3 prevents retinal ganglion cell apoptosis and mitigates microglia-mediated neuroinflammation in retinal ischemia-reperfusion injury.
The RPE-derived NF-κB/HO-1/MCP-1 pathway mediated Microglia Recruitment Involved in the Outer Blood-Retinal Barrier Breakdown in Experimental Diabetic Retinopathy.
Narirutin mitigates neuroinflammation following traumatic brain injury and modulates microglial polarization via the JAK2/STAT3 signaling pathway.
11-keto-β-boswellic acid and Z-guggulsterone suppress HMGB1/TLR4 pathway activity and modulate microglial polarization to remodel perineuronal nets after nerve injury.
Non-invasive bioelectrical therapy suppresses retinal neovascularization by modulating cellular metabolism and inflammation.
Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.
Microglial Necroptosis Mediated by RIPK3 Leads to Retinal Ganglion Cell Apoptosis Through the Release of FGF2 After Ischemia/Reperfusion.
Radial astroglia cooperate with microglia to clear neuronal cell bodies during zebrafish optic tectum development.

Nature. 2025 Nov 05.

Lymphoid gene expression supports neuroprotective microglia function.

Pinar Ayata, Jessica M Crowley, Matthew F Challman, Vinaya Sahasrabuddhe, Maud Gratuze, Sebastian Werneburg, Diogo Ribeiro, Emma C Hays, Violeta Durán-Laforet, Travis E Faust, Philip Hwang, Francisco Mendes Lopes, Chrysa Nikopoulou, Sarah Buchholz, Robert E Murphy, Taoyu Mei, Anna A Pimenova, Carmen Romero-Molina, Francesca Garretti, Tulsi A Patel, Claudia De Sanctis, Angie V Ramirez Jimenez, Megan Crow, Felix D Weiss, Jason D Ulrich, Edoardo Marcora, John W Murray, Felix Meissner, Andreas Beyer, Dan Hasson, John F Crary, Dorothy P Schafer, David M Holtzman, Alison M Goate, Alexander Tarakhovsky, Anne Schaefer.

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

DOI: https://doi.org/10.1038/s41586-025-09662-z
Signal Transduct Target Ther. 2025 Nov 03. 10(1): 360

Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.

Min Li, Shuang Chen, Rong Guo, Yang Wang, Mingrui Yang, Yingke Liu, Qiang Zhang, Shiyu Zhu, Jiaxin Li, Fang Chen, Bo Wang, Man Li, Qin He.

Dysregulated autophagy is a hallmark of Alzheimer's disease (AD), yet the extent of impairment in macroautophagy and chaperone-mediated autophagy (CMA) remains unclear. Here, we show that both pathways are disrupted in AD model mice, preceding β-amyloid accumulation and driving disease progression. However, therapeutic autophagy modulation is severely restricted by the blood-brain barrier (BBB). To overcome this, we developed Microglia-Liposome Fusion Extrusion (MiLi-FE), a method to engineer microglia-derived nanovesicles (AR@ENV) for the codelivery of AR7 (a CMA inducer) and rapamycin (a macroautophagy inducer). Leveraging its microglial membrane origin, AR@ENV effectively crosses the BBB and targets inflammatory sites in the AD brain, where it is internalized by neurons. Once inside, they synchronously activate both autophagy pathways: AR7 antagonizes retinoic acid receptor alpha (RARα) to enhance CMA, while rapamycin inhibits mTOR to promote macroautophagy. This coordinated activation enhances clearance of β-amyloid and other toxic aggregates, restores proteostasis, and provides robust neuroprotection. Furthermore, the strategy ameliorates neuroinflammation and significantly rescues cognitive deficits in two distinct AD mouse models. By integrating synchronized dual autophagy activation with targeted biomimetic delivery, AR@ENV represents a promising therapeutic candidate for AD. Moreover, the MiLi-FE platform offers a versatile and scalable approach for delivering diverse therapeutics to the central nervous system, extending its potential applicability to a range of neurological disorders.

DOI: https://doi.org/10.1038/s41392-025-02453-y
Nat Neurosci. 2025 Nov 06.

Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.

João Pedro Ferrari-Souza, Guilherme Povala, Nesrine Rahmouni, Bruna Bellaver, Pamela C L Ferreira, Marco Antônio De Bastiani, Douglas T Leffa, Firoza Z Lussier, Cristiano S Aguzzoli, Wagner S Brum, Giovanna Carello-Collar, Wyllians V Borelli, Joseph Therriault, Arthur C Macedo, Stijn Servaes, Jenna Stevenson, Ilaria Pola, Serge Gauthier, Diogo O Souza, Lucas Porcello Schilling, Mychael V Lourenco, Gallen Triana-Baltzer, Hartmuth C Kolb, Andréa L Benedet, Nicholas J Ashton, Dana L Tudorascu, Henrik Zetterberg, Kaj Blennow, Sterling C Johnson, Tharick A Pascoal, Pedro Rosa-Neto, Eduardo R Zimmer.

Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.

DOI: https://doi.org/10.1038/s41593-025-02103-0
Nat Commun. 2025 Nov 07. 16(1): 9846

Microglia alter sex-specific cerebellar myelination following placental hormone loss.

Jacquelyn Salzbank, Helene Lacaille, Jenah Gaby, Jiaqi J O'Reilly, Michael Kissner, Claire-Marie Vacher, Anna A Penn.

Placental dysfunction is linked to neurodevelopmental disorders, with males showing greater vulnerability to perinatal inflammation-mediated brain injuries. Using our transgenic mouse model, Akr1c14cyp19aKO (plKO), we investigate how reduced placental allopregnanolone (ALLO), an anti-inflammatory neurosteroid, contributes to sex-specific brain injury. plKO mice display sex-divergent cerebellar myelination and male-specific autism-like behaviors. Here we show that placental ALLO insufficiency triggers sex-divergent neuroinflammatory responses and microglial dysfunction. Sex-divergent differential expression of inflammatory genes and distinct inflammatory cytokine/chemokine patterns are seen in the placenta and the brain. Prostaglandin E2 (PGE2)-EP4 signaling is identified as a key regulator and, consistent with male plKO cerebellar hypermyelination, male microglial myelin phagocytosis is impaired by SIRPα-CD47 signaling changes. Postnatal manipulation of these critical pathways can normalize cerebellar myelin content and rescue abnormal behavior in male plKO mice. Sex-divergent microglial dysfunction and prostaglandin signaling drive male-biased neurodevelopmental impairments in our model, suggesting new therapeutic targets to improve brain development following placental dysfunction.

DOI: https://doi.org/10.1038/s41467-025-64814-z
Neuron. 2025 Oct 31. pii: S0896-6273(25)00810-4. [Epub ahead of print]

G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.

Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao.

DOI: https://doi.org/10.1016/j.neuron.2025.10.029
J Clin Invest. 2025 Nov 06. pii: e179985. [Epub ahead of print]

Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice.

Joseph A Barnes-Vélez, Xiaohong Zhang, Yaren L Peña Señeriz, Kiersten A Scott, Yinglu Guan, Jian Hu.

  Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs using cuprizone mediated demyelination coupled with conditional knockout of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional knockout (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, which features were largely absent in controls. Aberrant lipid processing was accompanied by elevated lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and necessary for enabling a pro-remyelinating environment.

Keywords:  Cell biology; Demyelinating disorders; Inflammation; Macrophages; Neuroscience

DOI:  https://doi.org/10.1172/JCI179985
Brain Behav Immun. 2025 Oct 30. pii: S0889-1591(25)00398-8. [Epub ahead of print] 106156

Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder.

Fulton T Crews, Liya Qin, Leon Coleman, Elena Vidrascu, Ryan Vetreno.

  Reactive microglia are associated with multiple brain diseases that may have specific disease-related phenotypes. Studies of human cortical microglia in alcohol use disorder (AUD) have characterized reactive microglial subtypes by transcriptome or histology. Preclinical studies have found proinflammatory signaling and microglia contribute to increases in alcohol drinking and preference, behaviors unique to AUD. This study of post-mortem human AUD combines microglial immunoreactivity (+IR) protein and changes in microglial gene expression (mRNA) in human orbital frontal cortex (OFC) in an effort to better characterize the reactive microglia associated with AUD. Since reactive microglia are linked to increased glial fibrillary acid protein (GFAP + IR) in reactive astrocytes, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG + IR), and neuron loss, these were determined as well. AUD reactive microglia were identified by increases in expression of multiple markers in the OFC compared to control moderate drinkers. Tmem119 + IR was decreased in AUD brain. Several of these microglial genes had parallel changes in + IR protein and mRNA. However, several microglial markers commonly used to identify reactive microglia did not show changes in mRNA, including Iba1, CD68, P2RY12, and CSF1R. Overall, AUD microglia show increases in monocyte phagocytic markers, but not TREM2, DAP, or complement genes. Reactive microglial markers were highly correlated with reactive astrocyte GFAP + IR, oxidative stress 8-OHdG + IR, as well as loss of neurons assessed using (Neuronal Nucleu [NeuN] and microtubule-associated protein 2 [MAP2] + IR). Mediation analysis indicated reactive microglia contribute to both reactive astrocytes and oxidative stress, but only reactive astrocytes were found to significantly contribute to loss of neurons (NeuN + IR). These findings are supported by mouse studies finding chronic ethanol exposure increases reactive astrocytes and oxidative stress that is inhibited by DREADD blockade of microglial activation. Our findings support a distinct AUD reactive microglial phenotype that activates astrocytes, contributing to AUD neurodegeneration and possibly heavy drinking.

Keywords:  Alcohol; Human cortex; Neurodegeneration; Reactive microglial phenotype

DOI:  https://doi.org/10.1016/j.bbi.2025.106156
Brain Behav Immun. 2025 Nov 04. pii: S0889-1591(25)00412-X. [Epub ahead of print] 106170

Targeting lysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing.

Lorenzo Barrella, María Pilar Ramírez-Ponce, Victoria Vázquez-Román, Marta San Millán-Huang, María Dolores Maldonado, Juan Antonio Flores-Cordero, Eva Alés.

  Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.

Keywords:  Brain ageing; Geroprotection; Ketotifen; Lysosomal acidification; Microglia; Neuroinflammation; Spatial memory

DOI:  https://doi.org/10.1016/j.bbi.2025.106170
Metab Brain Dis. 2025 Nov 03. 40(8): 304

Ferroptosis-inducing effects of cromolyn in microglia through NCOA4-mediated ferritinophagy.

Mustafa Kilic, Ceyhan Hacioglu, Sibel Tuncer, Ahmet Taskesen, Cengiz Tuncer.

  Cromolyn has anti-inflammatory and neuroprotective effects. However, its influence on microglial cell viability and death pathways remains largely unexplored. This study aimed to elucidate the cellular and molecular mechanisms underlying the effects of cromolyn exposure on microglial viability, with a particular focus on ferroptosis and ferritinophagy. HMC3 microglial cells were treated with cromolyn for 24, 48, and 72 h. Cell viability, nuclear morphology, cell cycle, MDA, GSH, and intracellular iron levels were assessed. Western blot analysis evaluated the expression of ferroptosis-related (GPX4, ACSL4, SLC7A11) and autophagy-associated (NCOA4, FTH1) proteins. Functional validation was performed using ferroptosis and autophagy inhibitors, and NCOA4-silencing. Cromolyn induced time- and dose-dependent cytotoxicity (IC₅₀ at 48 h = 9.4 µM), with prominent G0/G1 cell cycle arrest and nuclear abnormalities emerging at 48 h. At 72 h, excessive cell death limited mechanistic analyses. Cromolyn triggered ferroptosis via the GPX4-regulated pathway, evidenced by increased MDA, iron accumulation, and altered expression of GPX4, ACSL4, and SLC7A11. This ferroptotic response was mechanistically linked to NCOA4-mediated ferritinophagy, leading to GPX4 suppression and lipid peroxidation. NCOA4 knockdown rescued cell viability, restored FTH1 levels, and reduced lipid peroxidation. Our findings suggest, for the first time, that cromolyn may regulate microglial survival through an NCOA4-dependent ferritinophagy-ferroptosis axis. Given the dual roles of microglia in neuroinflammation and neurodegeneration, these data highlight both the therapeutic potential and risks of cromolyn in neurodegenerative disorders.

Keywords:  Cromolyn; Ferritinophagy; Ferroptosis; Microglia; NCOA4

DOI:  https://doi.org/10.1007/s11011-025-01729-0
J Neuroinflammation. 2025 Nov 07. 22(1): 263

Fatty acid-binding protein 4 drives microglia-mediated neuroinflammation through promoting S100A9 expression and lipid droplet accumulation after intracerebral hemorrhage.

Jiaqing He, Zijuan Qin, Haixiao Liu, Yaning Cai, Hao Wu, Tinghao Wang, Qing Hu, Yanni Xu, Pan Yang, Xun Wu, Yan Qu, Wei Guo.

   BACKGROUND: As primary immune sentinels of the central nervous system (CNS), microglia respond rapidly to acute brain injury and engage in dynamic crosstalk with infiltrating peripheral immune cells. This interplay critically shapes the neuroinflammatory microenvironment-a key determinant of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Fatty acid-binding protein 4 (FABP4), an adipokine associated with metabolic disorders, is recognized as a pivotal modulator of inflammatory responses; however, its role in ICH-induced SBI remains undefined.
OBJECTIVES: To investigate the pathogenic functions of FABP4 in microglia after ICH, elucidate its molecular mechanisms, and develop targeted therapeutic strategies.
METHODS: Blood and brain tissue samples from ICH patients were analyzed to evaluate the relationships between FABP4 expression and prognosis. Behavioral tests, Nissl staining, and Golgi-Cox staining were used to quantify neuronal damage. Immunofluorescence and flow cytometry were used to assess microglial activation and immune cell infiltration. Transcriptomic, proteomic, co-immunoprecipitation, western blotting, and ChIP‒qPCR analyses were used to examine the FABP4 regulatory network. Brain-targeted nanoparticles were engineered to deliver FABP4-specific siRNA.
RESULTS: Clinical analyses revealed microglia-specific FABP4 upregulation in ICH patients, correlating with poor neurological outcomes. Microglial Fabp4 knockout in mice attenuated neuronal loss, ameliorated cerebral edema, and enhanced functional recovery after ICH. Mechanistically, FABP4 promoted lipid droplet accumulation and inhibited the ubiquitin-proteasome-mediated degradation of S100A9 in microglia, synergistically amplifying neuroinflammation. Moreover, the activity of FABP4 in microglia facilitated neutrophil transendothelial migration into the brain parenchyma, exacerbating injury via the release of neutrophil extracellular traps (NETs). Finally, pharmacological FABP4 inhibition using brain-targeted nanoparticles conferred significant neuroprotective effects in ICH models.
CONCLUSION: This study establishes that FABP4 acts as a novel orchestrator of post-ICH neuroinflammation through dual enzymatic and nonenzymatic pathways. We also demonstrate a targeted nanotherapeutic strategy to suppress FABP4 and improve neurological outcomes.

Keywords:  FABP4; Intracerebral hemorrhage; Lipid droplet; Microglia; Neutrophil; S100A9

DOI:  https://doi.org/10.1186/s12974-025-03573-6
J Neuroinflammation. 2025 Nov 01. 22(1): 256

Inflammation associated microglial expansion disrupts hippocampal glial network communication, driving postoperative neurocognitive impairment.

Yuxiang Zheng, Wenjie Xu, Zizheng Suo, Yinyin Qu, Lina Lin, Enze Zhang, Dengyang Han, Meikui Wu, Hongyi Li, Hui Zheng, Ting Xiao, Cheng Ni.



Keywords:  Glial network communication; Inflammation associated microglia; Postoperative neurocognitive impairment; Single cell RNA sequencing; Tumor necrosis factor

DOI:  https://doi.org/10.1186/s12974-025-03566-5
J Neuroinflammation. 2025 Nov 04. 22(1): 258

Targeting hypercoagulability in ischemic stroke modulates fibrin-driven microglial polarization via JAK-STAT pathway.

Siyu Guan, Taoyuan Lu, Lei Li, Yong Zhang, Chuan Huang, Chen Li, Bowen Li, Jiayi Hu, Chunxiao Wan.

  Ischemic stroke is a leading cause of mortality and disability worldwide, yet its pathophysiological mechanisms remain poorly understood. In this study, we analyzed the coagulation function in 60 patients with acute ischemic stroke and found that their blood was in a hypercoagulable state. We confirmed this hematological change using a middle cerebral artery occlusion/reperfusion (MCAO/r) mouse model and improved the hypercoagulable state with the synthetic peptide Arg-Gly-Asp-Cys (RGDC), which inhibits platelet aggregation and fibrinogen binding. Interestingly, in MCAO/r mice, RGDC treatment led to enhanced neurological function, reduced blood-brain barrier (BBB) disruption, and alleviated neuroinflammation. Further analysis revealed that fibrin, the end product of coagulation, binds to ITGB2 on primary microglia and activates the JAK-STAT signaling pathway, influencing microglial polarization. These results establish a novel link between the hypercoagulable state and microglial function, offering a promising therapeutic approach to reduce neuroinflammation, improve neurological function and enhance outcomes in ischemic stroke by targeting coagulation pathways.

Keywords:  Fibrin; Hypercoagulable state; ITGB2; Ischemic stroke; Microglia

DOI:  https://doi.org/10.1186/s12974-025-03582-5
Front Immunol. 2025 ;16 1671204

ATF3 prevents retinal ganglion cell apoptosis and mitigates microglia-mediated neuroinflammation in retinal ischemia-reperfusion injury.

Ningzhi Zhang, Tian Tian, Zhiyi Wang, Xuejun He, Wenye Cao, Wenxi Zhang, Yiqiao Xing, Ning Yang.

   Introduction: Neuroinflammation is a key pathological response involved in secondary optic nerve injury following retinal ischemia-reperfusion injury. The expression of activating transcription factor 3 (ATF3), a highly conserved protein, is rapidly induced post-injury and is crucial for regulating immunity and inflammation. The potential neuroprotective mechanisms, function, and therapeutic potential of ATF3 following retinal ischemia-reperfusion remain largely unexplored. In this study, we examined the expression and distribution of ATF3 and achieved the overexpression of ATF3 in mouse retina via injection of adeno-associated virus vectors.
Methods: Retinal ganglion cell survival was assessed using immunofluorescence staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation status and polarization of microglia and microglia-associated neuroinflammation were also evaluated. In addition, peripheral venous blood samples and aqueous humor were collected from 20 individuals, 10 patients with primary angle-closure glaucoma and 10 controls, to detect changes in ATF3 expression.
Results: ATF3 overexpression partially suppressed retinal ganglion cell apoptosis by activating the p-Akt pathway, inhibited microglial activation, reversed microglial M1/M2 polarization, and reduced the release of inflammatory factors by decreasing integrin CD11b expression. ATF3 overexpression improved retinal structure and function by regulating microglial behavior and decreased neuronal death post-retinal ischemia-reperfusion.
Discussion: ATF3 overexpression may be a potential therapeutic strategy for the management of retinal ischemia-reperfusion-associated neurodegenerative diseases.

Keywords:  ATF3; glaucoma; microglia; neuroinflammation; retinal ganglion cell; retinal ischemia-reperfusion

DOI:  https://doi.org/10.3389/fimmu.2025.1671204
Exp Cell Res. 2025 Oct 30. pii: S0014-4827(25)00413-6. [Epub ahead of print] 114813

The RPE-derived NF-κB/HO-1/MCP-1 pathway mediated Microglia Recruitment Involved in the Outer Blood-Retinal Barrier Breakdown in Experimental Diabetic Retinopathy.

Yiyang Shu, Dandan Liu, Hai Xie, Chaoyang Zhang, Yanlong Bi, Jingfa Zhang.

   PURPOSE: To investigate the mechanisms underlying the microglia recruitment and its causal role in the breakdown of the outer blood-retinal barrier (oBRB) in diabetic retinopathy (DR).
METHODS: The Sprague-Dawley rats were adopted to establish diabetic model by intraperitoneal injection of streptozotocin. Twelve weeks later, the retinal pigment epithelium (RPE)-choroid complexes and retinal paraffin sections were examined with immunofluorescence. RNA-sequencing was performed on glyoxal-treated ARPE-19 cells, followed by bioinformatic analysis to identify significant genes and pathways. Transwell assays were employed to establish the co-culture system and investigate the interactions between ARPE-19 and BV2 microglial cells. The results were further validated by the inhibitor or siRNAs targeting NF-κB, HO-1, and MCP-1.
RESULTS: In 12-week diabetic rat retinas, microglia cells were observed to accumulate in the vicinity of the RPE cells, accompanied by the disruption of ZO-1. The expressions of ZO-1 and occludin remained largely unchanged in ARPE-19 cells when treated with glyoxal alone. However, when co-cultured with BV2 microglial cells, the expression levels of ZO-1 and occludin in glyoxal-treated ARPE-19 cells were significantly decreased, which were effectively prevented by siMCP-1. Mechanistically, RNA-sequencing analysis revealed that the activation of the NF-κB/HO-1/MCP-1 pathway in glyoxal-treated ARPE-19 cells significantly contributed to the recruitment of microglia. The above effects were reversed by BAY 11-7082, siHO-1 or siMCP-1.
CONCLUSION: Under diabetic condition, microglia are recruited by RPE cells via the NF-κB/HO-1/MCP-1 pathway, which subsequently result in the oBRB breakdown. This study provides a novel mechanistic insight for the interaction between microglia and RPE cells, and implies a potential therapeutic strategy for the treatment of DR.

Keywords:  Diabetic retinopathy; Microglia; NF-κB/HO-1/MCP-1 pathway; Outer blood-retinal barrier; RPE

DOI:  https://doi.org/10.1016/j.yexcr.2025.114813
Front Neurol. 2025 ;16 1680790

Narirutin mitigates neuroinflammation following traumatic brain injury and modulates microglial polarization via the JAK2/STAT3 signaling pathway.

Hebo Zhang, Junming Han, Chaolong Yan, Jiannan Mao, Huiying Yan, Wei Jin.

   Background: Traumatic brain injury (TBI) causes irreversible cerebral damage characterized by neuroinflammation and neuronal injury, representing a critical factor contributing to poor prognosis in TBI patients. While existing studies have demonstrated Narirutin's (Nar) neuroprotective effects in Parkinson's disease, research on Nar in the context of traumatic brain injury remains markedly limited. This investigation elucidates Nar's protective mechanisms in murine TBI models.
Methods: The behavioral tests of TBI model mice were conducted using the Morris water maze method. HE staining, Nissl staining and immunohistochemistry were performed. Western blotting was used to detect inflammatory indicators, and immunofluorescence was used to detect microglial polarization.
Results: Nar significantly reduced the inflammatory response and abnormal activation of signaling pathways induced by TBI. This effect is achieved by reducing the expression levels of NLRP3, IL-1β, and IL-6, promoting M2 polarization in microglia, and inhibiting the phosphorylation of JAK and STAT within the TBI model.
Conclusion: In conclusion, our research results indicate that Nar can improve neuroinflammation in TBI model mice, demonstrating excellent anti-inflammatory effects and neuroprotective properties, providing potential therapeutic strategies for the clinical treatment of TBI.

Keywords:  JAK2/STAT3 pathway; Narirutin; microglia; neuroinflammation; traumatic brain injury

DOI:  https://doi.org/10.3389/fneur.2025.1680790
J Adv Res. 2025 Nov 02. pii: S2090-1232(25)00867-7. [Epub ahead of print]

11-keto-β-boswellic acid and Z-guggulsterone suppress HMGB1/TLR4 pathway activity and modulate microglial polarization to remodel perineuronal nets after nerve injury.

Yucheng Liao, Le Yang, Yi Ding, Chao Guo, Junping Hu, Xinliang Xu, Hui Zhu, Jianhua Yang, Minggao Zhao.

   INTRODUCTION: Remodeling of perineuronal nets is an emerging strategy for treating neuropathic pain (NP) and aligns with the traditional Chinese medicine concept of dispersing blood stasis dispersion and dredging collateral channels. Frankincense and myrrh are known for their ability to promote blood circulation, eliminate blood stasis, unblock collateral channels, and relieve pain. However, the precise pharmacological components and mechanisms underlying their analgesic effects remain unclear.
OBJECTIVES: This study aimed to clarify the mechanisms of action of 11-keto-β-boswellic acid (KBA, a component of frankincense) and Z-Guggulsterone (Z-GS, a component of myrrh) in remodeling perineuronal nets.
METHODS: An NP model was developed via sciatic nerve chronic constriction injury (CCI), and possible targets and pathways were identified through transcriptomic analysis. To assess the effects of blocking the HMGB1/TLR4 signaling pathway on NP, the HMGB1 inhibitor BoxA and the TLR4 antagonist LRU were administered intrathecally. Additionally, KBA and Z-GS were administered via intraperitoneal injection for 14 days. The influence of KBA and Z-GS on perineuronal net remodeling via microglia polarization through HMGB1/TLR4 signaling was then investigated.
RESULTS: Transcriptomic analysis suggested that HMGB1/TLR4-induced neuroinflammation may play a role in NP. Intrathecal BoxA and LRU administration significantly decreased mechanical and thermal pain sensitivity levels in CCI mice, promoted microglia polarization by modulating neuroinflammation, and reversed perineuronal net degradation. Further analyses revealed that combining KBA and Z-GS resulted in a more pronounced reduction in mechanical and thermal pain sensitivities, downregulation of HMGB1, TLR4, MyD88, p-P65, and TRPV1 in microglia of the spinal dorsal horn, and enhanced microglia polarization, ultimately facilitating perineuronal net remodeling.
CONCLUSION: KBA and Z-GS alleviate NP in a combined effects, likely through inhibition of the HMGB1/TLR4 signaling pathway, which regulates microglia polarization and promotes perineuronal net remodeling. This suggests that targeting HMGB1/TLR4 signaling may be a promising means of treating NP.

Keywords:  HMGB1/TLR4 pathway; Microglia; Nerve injury; Neuropathic pain; Perineuronal nets

DOI:  https://doi.org/10.1016/j.jare.2025.10.072
Cell Commun Signal. 2025 Nov 06. 23(1): 479

Non-invasive bioelectrical therapy suppresses retinal neovascularization by modulating cellular metabolism and inflammation.

Anton Lennikov, Menglu Yang, Farris Elzaridi, Daisy Y Shu, Zhengping Hu, William P Miller, Matthijs Tsonas, Lu Huang, Christina Yen, Karen Chang, Julie Chen, Aruvi Vijikumar, Ajay Ashok, Kin-Sang Cho, Magali Saint Geniez, Darlene A Dartt, Dong Feng Chen.

   BACKGROUND: Pathological retinal neovascularization, a major cause of blindness, occurs in conditions such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Microglial activation and chronic neuroinflammation play critical roles in disease progression by promoting vascular permeability and angiogenesis. While anti-VEGF therapies are the current standard of care, their efficacy is limited, requiring frequent intraocular injections and raising concerns about long-term retinal health. Noninvasive transpalpebral electrical stimulation (TpES) has emerged as a potential alternative therapy, but its mechanism and therapeutic impact remain poorly understood.
METHODS: To investigate the therapeutic effects of TpES, we applied daily microcurrent stimulation (300 µA, 20 Hz, 4 min) in laser-induced choroidal neovascularization (CNV) and streptozotocin (STZ)-induced DR mouse models. Vascular pathology was assessed using fluorescein angiography, optical coherence tomography (OCT), and immunohistochemistry. Mechanistic studies were conducted using primary microglia and human retinal endothelial cells (HREC) to evaluate TpES-induced changes in intracellular calcium ([Ca²⁺]i) signaling, mitochondrial membrane potential, and ATP production. Additionally, human RPE/choroidal explants from healthy, AMD, and DR donors were cultured to assess TpES effects on angiogenesis in healthy and pathological human tissues.
RESULTS: TpES significantly reduced vascular leakage (by ~ 30%, p < 0.001) and lesion size in the CNV model (p < 0.05), while also suppressing microglial infiltration and VEGF-A expression. In the DR model, TpES attenuated microaneurysm formation, preserved endothelial tight junctions (in vitro). Mechanistic studies revealed that TpES suppressed ATP-induced microglial activation by reducing mitochondrial membrane potential and intracellular ATP levels, leading to depletion of ER calcium stores and inhibition of proinflammatory and proangiogenic signaling. TpES also directly suppressed endothelial cell migration and tube formation, as well as angiogenic sprouting in human RPE/choroidal explants.
CONCLUSIONS: These findings establish TpES as a dual-action therapy that mitigates both inflammation and pathological angiogenesis by modulating microglial and endothelial metabolism. Given its noninvasive nature and ability to target key pathways in retinal pathology, TpES represents a promising therapeutic strategy for AMD, DR, and other retinal vascular diseases.

Keywords:  Angiogenesis; Ca2+ signaling; Electrical stimulation; Microglia; Mitochondria; Retinal endothelial cells

DOI:  https://doi.org/10.1186/s12964-025-02451-1
Front Bioeng Biotechnol. 2025 ;13 1672520

Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.

Maria Cristina Ceccarelli, Luigi Lai, Alessio Carmignani, Matteo Battaglini, Gianni Ciofani.

  Neuroinflammation is a central feature of numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease, where excessive activation of microglia can contribute to neuronal damage. The pro-inflammatory M1 phenotype of microglia is characterized by increased production of reactive oxygen species (ROS), overexpression of surface markers such as CD40 and CD86, and secretion of cytokines like IL-6, IL-8, and TNF-α, all of which exacerbate oxidative stress and neurodegeneration. The development of strategies to control and tune microglial pro-inflammatory activation is therefore critical for reducing the progression of these conditions. In this study, the potential of polydopamine nanoparticles (PDNPs) as novel immunomodulatory agents for attenuating M1 microglial polarization was investigated. PDNPs were synthesized via a simple and reproducible protocol and thoroughly characterized in terms of size, morphology, hydrodynamic diameter, and surface charge, confirming their uniformity and stability. Biocompatibility assays showed that PDNPs are well tolerated by human microglial clone 3 (HMC3) cells, with minimal cytotoxicity even at relatively high concentrations. Confocal microscopy and flow cytometry analyses demonstrated efficient internalization of PDNPs by microglia, with preferential accumulation in lysosomal compartments and negligible mitochondrial localization. To mimic neuroinflammatory conditions, HMC3 cells were stimulated with interferon-gamma (IFN-γ), which significantly increased intracellular ROS levels, surface expression of CD40 and CD86, and secretion of pro-inflammatory cytokines. The co-treatment with PDNPs effectively mitigated these effects by reducing oxidative stress, suppressing the upregulation of M1 markers, and decreasing cytokine release, thereby preventing the shift toward a pro-inflammatory state. The results of this work demonstrate that PDNPs not only exhibit excellent biocompatibility and cellular uptake but also provide a robust means of counteracting IFN-induced microglial activation. These results establish PDNPs as promising nanoplatforms for modulating neuroinflammation and microglial activation. This study highlights the potential of PDNPs for future applications in the treatment of neurodegenerative diseases.

Keywords:  antioxidant; immunomodulation; microglia; neuroinflammation; polydopamine nanoparticles

DOI:  https://doi.org/10.3389/fbioe.2025.1672520
J Mol Neurosci. 2025 Nov 07. 75(4): 148

Microglial Necroptosis Mediated by RIPK3 Leads to Retinal Ganglion Cell Apoptosis Through the Release of FGF2 After Ischemia/Reperfusion.

Jian Liu, Anping Ma, Guangyi Huang, Wen Hu, Xin Xu, Rong Huang, Yaguang Hu, Qiaochu Cheng, Yanlin Feng, Dan Ye, Fan Xu, Aimin Sang.

  The aim of this study was to explore the function of receptor-interacting protein kinase 3 (RIPK3) on retinal neuron damage induced by retinal ischemia/reperfusion (IR). Microglia-specific RIPK3 knockout (KO) mice were employed to establish retinal IR models. Retinal structural and functional status was assessed using hematoxylin and eosin staining along with electroretinogram. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was employed to detect the situations of apoptotic cell death. Immunofluorescence and western blot were applied to detect the proteins associated with necroptosis and retinal inner neurons. Following retinal IR, necroptosis-related protein RIPK3 became activated within microglia, inducing the activation of mixed lineage kinase domain-like protein (MLKL). RIPK3 KO significantly alleviated IR-induced retinal morphological defects and protected against IR-induced visual dysfunction by preserving neurons within the retina. Additionally, the counts of TUNEL+ apoptotic cells were markedly reduced within RIPK3 KO mice after IR, along with a decrease in retinal inflammatory responses. Mechanistically, IR injury promoted retinal ganglion cells (RGCs) death by activating RIPK3 to induce MLKL and fibroblast growth factor 2 (FGF2) activation; however, RIPK3 KO suppressed this process. After IR, RIPK3-mediated necroptosis in microglia induced its activation, promoting inflammatory responses and thereby facilitating RGCs death. Targeting RIPK3 could protect retinal neurons from injury after IR through suppressing the MLKL/FGF2 pathway, rendering this a potential curative measure for RGCs degeneration in ischemic retinopathy.

Keywords:  Ischemia/reperfusion; Necroptosis; Neuronal injury; RIPK3; Retinal ganglion cells

DOI:  https://doi.org/10.1007/s12031-025-02429-1
Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01280-X. [Epub ahead of print]44(11): 116509

Radial astroglia cooperate with microglia to clear neuronal cell bodies during zebrafish optic tectum development.

Heather M Barber, Cassidy G Robbins, Zachary Cutler, Robin I Brown, Lauren E Jung, Inge Werkman, Sarah Kucenas.

  The clearance of dead cells by phagocytes is an essential component of neural development in many organisms. Microglia are the main phagocytes in the central nervous system (CNS), but the extent of participation by other glial cells remains unclear, especially under homeostatic conditions. During zebrafish optic tectum (OT) development, we observed radial astroglia forming dynamic, spherical projections from their basal processes. These projections, which we call scyllate heads, coincide with a wave of neuronal cell death in the OT. We show that scyllate heads surround the majority of dying neurons soon after phosphatidylserine exposure. However, unlike traditional phagosomes, scyllate heads persist for many hours and are rarely acidified or internalized. Instead, microglia invade scyllate heads and remove their contents for degradation. Our study reveals an active role for radial astroglia in homeostatic cell clearance and cooperation between microglia and radial astroglia during zebrafish OT development.

Keywords:  CP: Developmental biology; CP: Neuroscience; astrocyte; astroglia; glia; microglia; neural development; optic tectum; phagocytosis; programmed cell death; radial glia; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.116509