bims-microg 2025-07-27 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–07–27
23 papers selected by
Marcus Karlstetter, Universität zu Köln

Spatial proteomics of Alzheimer's disease-specific human microglial states.
Spatial map of microglial diversity beyond proteopathy.
Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice.
Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury.
Attenuation of Ca2+ signaling by overexpression of PMCA2 affects the microglial response to pathological events.
Prenatal alcohol exposure induces microglia to release exosomes with an elevated level of MIP-1α that participates in apoptotic process of stress-regulatory proopiomelanocortin neurons via glutamate excitotoxicity.
Microglia-Mediated Pathological Retinal Angiogenesis Leading to Visual Impairment in Mice Exposed to Perfluorooctanoic Acid.
Sex differences on laser-induced choroidal neovascularization and short-chain fatty acid treatment in a mouse model.
Transcriptomic profile of microglia following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats suggests strong contribution to neutrophil chemotaxis and activation.
Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson's disease.
Photoreceptor loss does not recruit neutrophils despite strong microglial activation.
AKT signaling upregulates BDNF expression in induced neural stem cells that interact with microglia.
Metabolic stress and early cell death in photoreceptor precursor cells following retinal transplantation.
Microglial clock dysfunction during neuroinflammation impairs oligodendrocyte progenitor cell recruitment and disrupts neuroimmune homeostasis.
Botulinum toxin type A inhibits microglia pyroptosis by suppressing Cblb-mediated degradation of Pdlim1 to attenuate neuropathic pain.
Lars2 Deficiency-Induced Mitochondrial Dysfunction Drives the Emergence of a Pro-Inflammatory Stroke-Specific Microglial Subpopulation.
Suppression of TRPV5 Regulates Microglia-Mediated Neuroinflammation Following Status Epilepticus.
ULK1 Knockout Exacerbates Ischemia-Induced Microglial Dysfunction via TRAF6/NF-κB Signaling Pathway.
Pantothenic acid-mediated inhibition of microglial inflammation via the JAK2/STAT3 pathway enhances motor function recovery after Spinal cord injury.
PD-1 Attenuates Neuropathic Pain by Ameliorating NLRP3 Inflammasome-Mediated Microglia Pyroptosis.
AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.
Artesunate suppresses ocular inflammation in endotoxin-induced uveitis through inhibiting the NF-κB signaling pathway and M1 macrophage polarization.
Key immune regulators in retinal ischemia-reperfusion injury via RNA sequencing.

Nat Immunol. 2025 Jul 22.

Spatial proteomics of Alzheimer's disease-specific human microglial states.

Dunja Mrdjen, Bryan J Cannon, Meelad Amouzgar, YeEun Kim, Candace Liu, Kausalia Vijayaragavan, Christine Camacho, Angie Spence, Erin F McCaffrey, Anusha Bharadwaj, Dmitry Tebaykin, Syed Bukhari, Marc Bosse, Felix J Hartmann, Adam Kagel, John Paul Oliveria, Koya Yakabi, Geidy E Serrano, Maria M Corrada, Claudia H Kawas, Robert Tibshirani, Thomas G Beach, M Ryan Corces, Will Greenleaf, R Michael Angelo, Thomas Montine, Sean C Bendall.

Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.

DOI: https://doi.org/10.1038/s41590-025-02203-w
Nat Immunol. 2025 Jul 24.

Spatial map of microglial diversity beyond proteopathy.

DOI: https://doi.org/10.1038/s41590-025-02205-8
Nat Commun. 2025 Jul 23. 16(1): 6779

Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice.

Yuming Wu, Yujing Zhang, Yuan Yu, Xin Wang, Zifan Zhen, Yin Yuan, Bing Xie, Mengqi Han, Mengyuan Wang, Xinyu Zhang, Xueqiang Sun, Xiaoyue Wen, Kenji Hashimoto, You Shang, Shiying Yuan, Jiancheng Zhang.

Sepsis is a severe global health issue with high mortality rates, and sepsis-associated encephalopathy (SAE) further exacerbates this risk. While recent studies have shown the migration of gut immune cells to the lungs after sepsis, their impact on the central nervous system remains unclear. Our research demonstrates that sepsis could induce the migration of IL-7Rhigh CD8low γδ T17 cells from the small intestine to the meninges, where they secrete IL-17A, impairing mitochondrial function in microglia and activating the cGAS-STING-C1q pathway in male mice. This process is accompanied by inhibited ubiquitination of STING at the K150 site, resulting in STING accumulation and increased release of C1q-tagged hippocampal synapses, which are subsequently pruned by activated microglia. Importantly, 4-octyl itaconate mitigates the excessive synaptic pruning by inhibiting γδ T17 cell migration and promoting STING ubiquitination, thereby alleviating SAE. Our findings suggest a potential mechanism of synaptic pruning by microglia via the cGAS-STING-C1q pathway, emphasize the critical role of gut-derived γδ T17 cell migration to the meninges in SAE, and highlight the importance of STING ubiquitination in modulating C1q-mediated excessive synaptic pruning.

DOI: https://doi.org/10.1038/s41467-025-62181-3
Brain Behav Immun. 2025 Jul 19. pii: S0889-1591(25)00284-3. [Epub ahead of print]

Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury.

Wei Song, Runhan Fu, Zhongze Yuan, Yanchun Liu, Yanbing Kao, Renjie Zhang, Guangjin Gu, Hanming Zhu, Haoyun Liu, Zhihao Zhang, Xiaohong Kong, Shiqing Feng.

  Spinal cord injury (SCI) leads to loss of motor and sensory function below the lesion site, presenting a lifelong burden of disability. During the acute phase of SCI, microglia develop an inflammatory phenotype, characterized by the NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation, exacerbating tissue damage and impeding trauma recovery. However, the molecular mechanisms underlying this process remain unclear. Here we show that conditional knockout of Nlrp3 in microglia using Nlrp3fl/fl; Cx3cr1-CreERT; Rosa26-tdTomato mice (Nlrp3ΔMG) confers neuroprotection by preserving neuron survival and mitigating tissue damage during the acute phase of SCI. Mechanistically, Nlrp3 ablation in microglia attenuates the activation of pyroptosis-related signaling pathways in microglia and suppresses the production of inflammatory cytokines (IL-1β, IL-18, CCL3, and CCL5). Furthermore, we identify RelA as a transcriptional regulator of Nlrp3, binding to its promoter and upregulating its expression in activated microglia. Inhibition of RelA using pyrrolidine dithiocarbamate ammonium (PDTC), a blood-brain barrier permeable drug, effectively downregulates NLRP3 expression and suppresses spinal cord inflammation, thereby contributing to neuroprotection. Our findings demonstrate the crucial role of RelA/NLRP3/CCL3 axis in modulating microglial inflammation and highlight its potential as a therapeutic target to promote recovery post SCI.

Keywords:  CCL3; Inflammatory response; Microglia; NLRP3; RelA; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bbi.2025.07.015
Brain Behav Immun. 2025 Jul 21. pii: S0889-1591(25)00282-X. [Epub ahead of print]

Attenuation of Ca2+ signaling by overexpression of PMCA2 affects the microglial response to pathological events.

Fan Zeng, Sagun Tiwari, Alaa Chok, Yan Zhou, Yue Zhao, Xuezhen Chen, Yue Hao, Kaichuan Zhu, Helmut Kettenmann, Xianyuan Xiang.

  Microglia strongly impact the pathologic course of brain diseases and injuries. Intracellular Ca2+ dynamics serve as central integrators, connecting microglial sensing capacity to their responses. We generated a mouse line with microglial overexpression of plasma membrane Ca2+-ATPase (PMCA)2, a central regulator of cytoplasmic Ca2+ homeostasis. This manipulation significantly attenuated ATP-evoked Ca2+ signals in vitro and spontaneous Ca2+ transients in vivo. Notably, in contrast to astrocytes, PMCA2 overexpression in microglia/macrophages did not affect animal behavior and survival. It had, however, a profound impact on microglial reactivity in pathological contexts, including reduced inflammatory responses following lipopolysaccharide challenge and diminished microglial proliferation at sites of acute injury. In an Alzheimer's disease model, PMCA2 overexpression attenuated the disease-associated microglial signature, reducing amyloid plaque burden and plaque-associated neuritic dystrophy. These findings highlight the importance of Ca2+-mediated signaling for modulating the microglial response to pathologic events. Attenuating microglial Ca2+ signaling by PMCA2 overexpression is a potential strategy to promote beneficial microglial phenotypes in brain inflammation or degeneration.

Keywords:  Alzheimer’s disease; Calcium signaling; Microglia; Neuroinflammation; PMCA2; Stab wound

DOI:  https://doi.org/10.1016/j.bbi.2025.07.013
Brain Behav Immun. 2025 Jul 19. pii: S0889-1591(25)00285-5. [Epub ahead of print]

Prenatal alcohol exposure induces microglia to release exosomes with an elevated level of MIP-1α that participates in apoptotic process of stress-regulatory proopiomelanocortin neurons via glutamate excitotoxicity.

Prashant Tarale, Shaista Chaudhary, Dipak K Sarkar.

  Microglia are known to participate in ethanol-activated neuronal death of stress-regulatory proopiomelanocortin (POMC) neurons in the hypothalamus leading to hyper corticosterone response to stress and anxiety-like behaviors in a rat model of fetal alcohol spectrum disorder. We recently reported that ethanol-activated microglia release small membrane-bound vesicles called exosomes, which carry various neuroinflammatory molecules involved in POMC neuronal death. Here, we determined if macrophage inflammatory protein (MIP)-1α, a neuroinflammatory chemokine participates in ethanol-induced POMC neuronal death during the developmental period. We used an in vitro model, consisting of primary culture of hypothalamic microglia prepared from postnatal day 2 (PND2) rat and treated with or without 50 mM ethanol for 24 h, and an in vivo animal model in which hypothalamic microglia were obtained from PND6 rats fed daily with 2.5 mg/kg ethanol or control milk formula between PND2-6. We found that ethanol elevated MIP-1α level in microglial exosomes both in vitro and in vivo models. Ethanol-activated microglial exosomes when introduced into primary cultures of β-endorphin-producing POMC neurons, increased cellular levels of MIP-1α and chemokine receptor CCR5 related signaling molecules including glutamate transporter-1 and NMDA receptor subunit genes, calcium influx, inflammatory cytokines and apoptotic genes causing apoptotic death of POMC neurons. These effect of microglial exosomes on POMC neurons were suppressed by a CCR5 antagonist Maraviroc. Maraviroc administrated in postnatal PAE rats, reduces the ethanol-induced death of POMC neurons in developing hypothalamus and suppressed stress-related corticosterone hyperresponse and anxiety-like behaviors during adulthood. These findings indicate that alcohol exposure during the developmental period increases MIP-1α levels in microglial exosomes, which activate CCR5 signaling and cause apoptosis in POMC neurons, leading to hormonal and behavioral stress response abnormalities in animals.

Keywords:  Anxiety behaviors; Ethanol; Exosomes; Fetal alcohol spectrum disorder; Hyper-stress response; MIP-1α; Microglia; POMC neurons

DOI:  https://doi.org/10.1016/j.bbi.2025.07.016
Environ Sci Technol. 2025 Jul 23.

Microglia-Mediated Pathological Retinal Angiogenesis Leading to Visual Impairment in Mice Exposed to Perfluorooctanoic Acid.

Meng Yuan, Tianxu Zhang, Yumeng Sun, Shujun Yi, Guoge Han, Pinghui Wei, Xuan Chen, Yan Wang, Lingyan Zhu.

  Increasing epidemiological evidence suggests that human visual impairment is associated with perfluoroalkyl and polyfluoroalkyl substances, although the underlying mechanisms remain unclear. In this study, we established a mouse model through a 28-day oral administration of perfluorooctanoic acid (PFOA) at doses of 3 and 15 mg/kg BW/day to investigate its impacts on pathological retinal angiogenesis, a hallmark of multiple vision-threatening diseases. PFOA exposure induced characteristic retinal acellular capillary formation, even in the normal avascular zone, accompanied by a hemorrhagic manifestation. Through integrated methodologies combining in vivo reactive oxygen species (ROS) quantification, retinal proteomics, and microglial phenotypic analysis, we demonstrated that PFOA compromises blood-retinal barrier integrity, resulting in ROS accumulation. This triggered a cascade involving nuclear factor-kappa B (NF-κB) activation, microglial proinflammatory response, proinflammatory cytokine release, cyclooxygenase-2 (COX-2) overexpression, and subsequent vascular endothelial growth factor A (VEGFA) hypersecretion. Complementary in vitro experiments further confirmed that PFOA treatment induced microglial activation by prompting NF-κB nuclear translocation, with activated microglia secreting VEGFA, which targets retinal microvascular endothelial cells to promote tube formation. Our work provides the first mechanistic insights into PFOA-induced retinal angiogenesis and highlights its potential role in visual impairment.

Keywords:  NF-κB; angiogenesis; microglia; perfluorooctanoic acid; retina

DOI:  https://doi.org/10.1021/acs.est.5c03180
J Neuroinflammation. 2025 Jul 19. 22(1): 188

Sex differences on laser-induced choroidal neovascularization and short-chain fatty acid treatment in a mouse model.

Chufan Yan, Caio Andreeta Figueiredo, Inga-Marie Pompös, Bilge Ugursu, Paula Arribas-Lange, Sergej Skosyrski, Seulkee Yang, Petra Althoff, Norbert Kociok, Antonia M Joussen, Susanne A Wolf.

  Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a clinical presentation that varies between sexes. In late-stage AMD, choroidal neovascularization (CNV) triggers retinal inflammation and degeneration, processes that are exacerbated by an overactive response of retinal microglial cells. Short-chain fatty acids (SCFAs) have emerged as potential treatments for AMD due to their anti-inflammatory properties. In this study, we investigate the effects of SCFA treatment in a laser-induced CNV mouse model, focusing on sex-dependent differences in disease progression and microglial response. Our findings demonstrate distinct sex-specific patterns in the development of CNV and associated pathological hallmarks. SCFA treatment resulted in a slight increase in density of Iba1+ microglial cells in females at 3 days post-laser (3dpl), while it prevented an increase in males at 7 dpl, with both sexes showing enhanced microglial ramification. The dynamics of microglial density were likely linked to protective effects on CNV lesion, leakage size, and inflammation, which occurred earlier in females and later in males. At transcriptional level, SCFA showed mixed effects, mainly targeting inflammation resolution, mitochondrial support, and neuronal repair in a sex-dependent manner. In vitro, SCFAs reduced microglial phagocytosis of retinal debris, suggesting a potential anti-inflammatory action. This study underscores the importance of considering sex-specific responses in the development of AMD treatments, such as SCFAs, and highlights the need for personalized therapeutic strategies.

Keywords:  Age-related macular degeneration; Choroidal neovascularization; Retinal microglia; Sex differences; Short-chain fatty acids

DOI:  https://doi.org/10.1186/s12974-025-03508-1
J Neuroinflammation. 2025 Jul 19. 22(1): 189

Transcriptomic profile of microglia following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats suggests strong contribution to neutrophil chemotaxis and activation.

Anna-Sophie Bremer, Nico Henschel, Hannah Burkard, Maria Eugenia Bernis, Thomas Ulas, Hemmen Sabir.

   BACKGROUND: Inflammation-sensitized hypoxic-ischemic brain injury significantly contributes to neonatal mortality as affected neonates do not benefit from standard cooling treatments. To get further insight into inflammatory responses involved, we experimentally investigated the immune response of microglia in an inflammation-sensitized neonatal hypoxia-ischemia (HI) model.
RESULTS: Transcriptomic analysis of microglia isolated from brains following inflammation-sensitized HI brain injury revealed a strong upregulation of leukocyte recruitment and pro-inflammatory markers. Specifically, markers associated with neutrophil-mediated immune responses and chemotaxis were upregulated in the inflammation-sensitized HI group compared to the non-inflammation-sensitized HI and control groups. Serpine 1 and Selp could be identified as specifically upregulated markers indicating an acute inflammatory condition before HI injury.
CONCLUSION: Our study revealed preliminary data about a microglia population which is primed to recruit peripheral neutrophils to infiltrate the brain and mediate neutrophil immune response. We showed a contribution to neutrophil activation in case of inflammation following HI in the brain. Targeting microglia-mediated neutrophil recruitment can indicate a possible treatment approach in case of inflammation-sensitized HI brain injury.

Keywords:  Brain inflammation; Microglia priming; Neonatal Hypoxia-Ischemia; Neutrophil recruitment; Transcriptomic analysis

DOI:  https://doi.org/10.1186/s12974-025-03516-1
J Neuroinflammation. 2025 Jul 19. 22(1): 190

Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson's disease.

Chunlei Han, Huizhi Wang, Moxuan Zhang, Liuliu Wu, Anni Wang, Pengda Yang, Yuan Gao, Chaonan Zhang, Jianing Gao, Tao Xue, Tingting Du, Yucheng Ji, Lin Shi, Chunkui Zhang, Renpeng Li, Yilei Xiao, Jianguo Zhang, Fangang Meng.



Keywords:  ACSL1; Lipid droplet; Microglia; Neuroinflammation; Parkinson’s disease; TBK1

DOI:  https://doi.org/10.1186/s12974-025-03517-0
Elife. 2025 Jul 22. pii: RP98662. [Epub ahead of print]13

Photoreceptor loss does not recruit neutrophils despite strong microglial activation.

Derek Power, Justin Elstrott, Jesse Schallek.

  In response to central nervous system (CNS) injury, tissue-resident immune cells such as microglia and circulating systemic neutrophils are often first responders. The degree to which these cells interact in response to CNS damage is poorly understood, and even less so, in the neural retina, which poses a challenge for high-resolution imaging in vivo. In this study, we deploy fluorescence adaptive optics scanning light ophthalmoscopy (AOSLO) to study microglia and neutrophils in mice. We simultaneously track immune cell dynamics using label-free phase-contrast AOSLO at micron-level resolution. Retinal lesions were induced with 488 nm light focused onto photoreceptor (PR) outer segments. These lesions focally ablated PRs, with minimal collateral damage to cells above and below the plane of focus. We used in vivo AOSLO, and optical coherence tomography (OCT) imaging to reveal the natural history of the microglial and neutrophil response from minutes to months after injury. While microglia showed dynamic and progressive immune response with cells migrating into the injury locus within 1 day after injury, neutrophils were not recruited despite close proximity to vessels carrying neutrophils only microns away. Post-mortem confocal microscopy confirmed in vivo findings. This work illustrates that microglial activation does not recruit neutrophils in response to acute, focal loss of PRs, a condition encountered in many retinal diseases.

Keywords:  adaptive optics; adaptive optics scanning laser ophthalmoscope; age-related macular degeneration; immunology; inflammation; leukocytes; mouse; neuroscience; scanning laser ophthalmoscopy; uveitis

DOI:  https://doi.org/10.7554/eLife.98662
Stem Cell Res Ther. 2025 Jul 21. 16(1): 392

AKT signaling upregulates BDNF expression in induced neural stem cells that interact with microglia.

Wenjia Wang, Wenqiao Qiu, Pengyu Chen, Zhijun Yang, Mingming Zou, Yuhui Zhou, Lili Guo, Dan Zou, Ruxiang Xu, Mou Gao.

   BACKGROUND: Brain-derived neurotrophic factor (BDNF) has the capacity to promote neuronal survival that is crucial to neurological recovery after closed head injury (CHI). We previously reported that intracerebral-transplanted induced neural stem cells (iNSCs) can up-regulate BDNF levels to exert neurotrophic effects in CHI-damaged brains. Here we aim to elucidate the mechanism of BDNF up-regulation in iNSCs.
METHODS: We performed iNSC and lipopolysaccharide (LPS)-activated microglia co-culture experiments, iNSC transplantation, loss-of-function study, morphological and molecular biological analyses to uncover the mechanism underlying the overexpression of BDNF in iNSCs.
RESULTS: Our results indicated that co-culture with LPS-activated microglia up-regulated the expression levels of BDNF, as well as Bdnf exons I and IV in iNSCs. Notably, AKT inhibition could counteract the effects of co-culture with LPS-activated microglia that decreased enhancer of zeste homolog 2 (EZH2) and H3K27 trimethylation (H3K27me3) levels at Bdnf promoter IV but increased EZH2 phosphorylation and BDNF expression in iNSCs. Additionally, blockage of AKT could counteract the effects of co-culture with LPS-activated microglia that increased cAMP response element binding protein (CREB) levels at Bdnf promoters I and IV, as well as CREB phosphorylation and BDNF expression in iNSCs. Furthermore, blocking AKT activity in grafted iNSCs could reduce BDNF expression in the injured cortices of CHI mice.
CONCLUSIONS: In short, our study shows that AKT signaling may regulate BDNF expression in iNSCs. Activation of AKT can up-regulate BDNF expression through inactivating EZH2 as well as reducing EZH2 and H3K27me3 levels at Bdnf promoter IV, meanwhile activating CREB as well as increasing CREB levels at Bdnf promoters I and IV.

Keywords:  AKT; BDNF; CREB; Closed head injury; EZH2; H3K27me3; Induced neural stem cell; Microglia

DOI:  https://doi.org/10.1186/s13287-025-04489-x
Stem Cell Res Ther. 2025 Jul 25. 16(1): 397

Metabolic stress and early cell death in photoreceptor precursor cells following retinal transplantation.

Raghavi Sudharsan, Natalia Dolgova, Jennifer Kwok, Alexa Gray, Yu Sato, Agustin Luz Madrigal, Praveen Joseph Susaimanickam, Emil Kriukov, Petr Baranov, John H Wolfe, Gustavo D Aguirre, David M Gamm, William A Beltran.

   BACKGROUND: Progressive photoreceptor loss in retinal degenerative diseases leads to irreversible vision impairment. Transplantation of human embryonic or induced pluripotent stem cell-derived photoreceptor precursor cells (PRPCs) offers potential for vision restoration. However, substantial early donor cell loss remains a major challenge. This study aims to elucidate the mechanisms underlying early PRPC loss and to evaluate host retinal responses to transplantation.
METHODS: PRPCs derived from human embryonic stem cells (hESC)-based retinal organoids were subretinally transplanted into both normal and degenerated canine retinas to investigate the impact of host retinal degeneration on transplant survival and integration. Single-cell RNA sequencing (scRNAseq) was performed on transplanted PRPCs 3 days post-transplantation into normal canine retinas, as well as on host retinal cells to identify molecular pathways associated with early donor cell loss. Non-invasive multimodal retinal imaging and immunohistochemical analyses were conducted to assess PRPC survival, integration, and host immune responses.
RESULTS: Despite systemic immunosuppression, extensive early loss of human PRPCs occurred within the first week following xenotransplantation into both normal and degenerated canine retinas, suggesting that factors beyond immune activation contribute to donor cell loss. Transcriptomic analysis identified metabolic stress as a key driver of early donor cell death, characterized by dysregulation of mitochondrial function and oxidative phosphorylation pathways. Microglial infiltration into the donor cell mass was also observed in normal retinas, suggesting a response to donor cell stress and apoptosis. Beyond the initial phase of cell death, surviving donor cells integrated and persisted when transplanted into retinas with a partially preserved outer nuclear layer, whereas cell loss continued when intervention occurred at end-stage degeneration.
CONCLUSIONS: Metabolic stress represents a critical barrier to PRPC survival following transplantation. Strategies aimed at enhancing metabolic resilience may improve transplantation outcomes. Furthermore, host retinal responses shape the transplant microenvironment, influencing donor cell survival and integration. These findings highlight the need for targeted interventions to mitigate early metabolic stress and optimize PRPC transplantation strategies for retinal degenerative diseases.

Keywords:  Metabolic stress; Photoreceptor precursor cells; Retinal degenerative diseases; Retinal transplantation; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s13287-025-04509-w
Front Immunol. 2025 ;16 1620343

Microglial clock dysfunction during neuroinflammation impairs oligodendrocyte progenitor cell recruitment and disrupts neuroimmune homeostasis.

Qingqing Lu, Jin Young Kim.

   Introduction: Circadian clocks generate daily physiological rhythms and regulate immune functions, including cytokine production and inflammatory responses. Although time-of-day-dependent variation in microglial immune activity has been reported, how intrinsic microglial clocks respond to neuroinflammatory stimuli and influence microglial function remains unclear.
Methods: We induced neuroinflammation via intraperitoneal injection of lipopolysaccharide (LPS) and isolated microglia from control and LPS-treated mouse brains. To examine circadian clock dynamics and downstream targets, we performed time-series gene expression analyses. To assess the functional relevance of microglial clocks, we transplanted either wild-type or Bmal1-deleted microglia, as well as control or neuroinflammatory microglia, into the corpus callosum of NG2DsRed reporter mice and evaluated oligodendrocyte progenitor cell (OPC) recruitment.
Results: LPS-induced neuroinflammation triggered a phase shift in the core clock gene Bmal1 and disrupted the rhythmic expression of its targets, including Per1, Iba1, Itgam, and Ccl5, resulting in sustained microglial activation. Transplanted wild-type microglia effectively recruited OPCs, whereas both Bmal1-deleted and neuroinflammatory microglia failed to recruit OPCs, indicating that disrupted microglial clock function promotes persistent activation and impairs glial-glial communication.
Discussion: These findings identify microglial circadian clocks as key regulators of homeostatic function and glial-glial communication. Preserving intrinsic clock function in microglia may represent a strategy to mitigate neuroinflammatory damage and support white matter integrity.

Keywords:  circadian clocks; glial-glial communication; microglia; microglial homeostasis; neuroinflammation; oligodendrocyte progenitor cells

DOI:  https://doi.org/10.3389/fimmu.2025.1620343
J Headache Pain. 2025 Jul 22. 26(1): 165

Botulinum toxin type A inhibits microglia pyroptosis by suppressing Cblb-mediated degradation of Pdlim1 to attenuate neuropathic pain.

Sheng Tian, Lanxiang Wu, Heqing Zheng, Zhijuan Cheng, Jingjing Liu, Mingxu Liu, Xinping Yu, Jianglong Tu, Wei Wu.

   BACKGROUND: Microglia pyroptosis, a newly identified form of inflammatory cell death, is involved in the development of neuropathic pain (NP). Botulinum toxin type A (BTX-A) has been shown to be effective in relieving NP, but the mechanisms involved have not been clarified.
METHODS: A mice model of NP was established with chronic constriction injury (CCI) method. The expression levels of key molecules and the extent of microglia pyroptosis were assessed using RT-qPCR, western blot, ELISA and immunofluorescence. Moreover, lipopolysaccharide (LPS) was used in vitro to induce pyroptosis of microglia to explore the potential molecular mechanisms of BTX-A.
RESULT: In a mice model of NP, BTX-A administration increased the pain threshold and decreased the Cblb protein expression level, consistent with the results of in vitro experiments. Functional experiments and mouse models were respectively used to evaluate the severity of microglia pyroptosis. The results showed that BTX-A inhibited microglia pyroptosis through Cblb protein. Subsequently, mass spectrometry (MS) analysis and immunoprecipitation were conducted to identify proteins interacting with Cblb. The results identified Pdlim1 was a potential interacting partner of Cblb, which regulats the ubiquitination of Pdlim1. Mechanically, Cblb binds to the PDZ and LIM domains of Pdlim1 and then targets Pdlim1 at K244 for ubiquitination and proteasome-mediated degradation. Pdlim1 knockdown lentiviral plasmid was constructed and stable Pdlim1 knockdown microglial cell lines were established for rescue experiments. The results demonstrated that BTX-A suppresses microglia pyroptosis via Pdlim1/NF-κB signaling axis. Finally, intrathecal injection of adeno-associated virus overexpressing Cblb was used in rescue experiments. The results confirmed that BTX-A attenuates neuropathic pain via the Cblb/Pdlim1/NF-kB signaling axis.
CONCLUSIONS: This study demonstrates that BTX-A suppresses the activity of Cblb, thereby reducing Pdlim1 protein degradation, inhibiting the NF-kB pathway, and ultimately mitigating microglia pyroptosis. Our findings suggest that Cblb could serve as a novel therapeutic target for BTX-A in the treatment of NP.

Keywords:  BTX-A; Cblb; Microglia pyroptosis; Neuropathic pain

DOI:  https://doi.org/10.1186/s10194-025-02109-w
Aging Dis. 2025 Jul 04.

Lars2 Deficiency-Induced Mitochondrial Dysfunction Drives the Emergence of a Pro-Inflammatory Stroke-Specific Microglial Subpopulation.

Qing Zou, Jianxin Zhou, Ying Li, Jiaming Shi, Jingying Huang, Cheng Zhuang, Hao Wu, Huanle Hong, Yanan Guo, Qian Li, Robert Chunhua Zhao, Jiao Wang.

Stroke significantly alters microglial immune status beyond the traditional M1/M2 classification. We analyzed single-cell RNA sequencing data from the striatum of hemorrhagic, ischemic, and control mice, revealing activation of mitochondrial autophagy and assembly processes after stroke. Gene Ontology functional enrichment analysis indicated that stroke-associated genes predominantly regulate mitochondrial maintenance, with leucyl-tRNA synthetase 2 (Lars2) markedly upregulated in post-stroke microglia. A distinct microglial subset (Mc) was identified with notably low Lars2 expression. In vitro, Lars2 overexpression enhanced mitochondrial function, reduced pro-inflammatory cytokine release, and suppressed Mc marker gene expression. Cell-cell communication analysis revealed Mc as the most interactive microglial subset following stroke, particularly engaging with neurons. Among neuron-Mc signaling pairs, the neurotrophic factor pleiotrophin-syndecan-4 (PTN-SDC4) ligand-receptor pair emerged as a key mediator. Conditioned media from stressed microglia upregulated neuronal Ptn expression, likely recruiting microglia, as exogenous PTN promoted microglial migration. These findings identify Mc as a stroke-induced microglial population with low Lars2 expression and pro-inflammatory features. The lack of compensatory mitochondrial repair in Mc contributes to pro-inflammatory polarization, positioning Lars2 as a mitochondrial checkpoint linking stroke-induced microglial reprogramming to neuroinflammation.

DOI: https://doi.org/10.14336/AD.2025.0387
Glia. 2025 Jul 24.

Suppression of TRPV5 Regulates Microglia-Mediated Neuroinflammation Following Status Epilepticus.

Soojin Park, Se Hoon Kim, Chul Hoon Kim, Kyoung Hoon Jeong, Won-Joo Kim.

  Neuroinflammation, predominantly associated with glial activation and the release of various inflammatory mediators, is a vital hallmark of the pathophysiology of epilepsy. Numerous studies have indicated that identifying novel factors that diminish neuroinflammatory processes may be important for developing effective therapeutic strategies to prevent neuropathological processes and epileptogenic progression. Transient receptor potential vanilloid 5 (TRPV5) is a highly selective calcium ion channel belonging to the TRPV family. TRPV5 expression has been identified in diverse regions of the brain; however, it remains unknown how TRPV5 is implicated in the pathophysiological features of neurological diseases, including epilepsy. Herein, we show that TRPV5 expression is upregulated in the hippocampus of a pilocarpine-induced status epilepticus (PCSE) model, predominantly in activated microglia. Pharmacological inhibition of TRPV5 using econazole attenuated microglial activation, as indicated by the shift of LPS-stimulated primary hippocampal microglia to a resting state. This inhibition suppressed AKT/NF-κB signaling, reduced NLRP3 inflammasome activity, and decreased proinflammatory cytokine production. Additionally, TRPV5 inhibition reduced hippocampal microglial activation and neuroinflammation following PCSE. These findings suggest that TRPV5 contributes to the regulation of microglial activation, resulting in the suppression of microglia-derived neuroinflammation during the sub-acute phase of epilepsy. In conclusion, the present study suggests that targeting TRPV5 may offer a novel therapeutic approach to managing the neuroinflammatory processes during epileptogenic progression.

Keywords:  TRPV5; econazole; microglia; neuroinflammation; status epilepticus

DOI:  https://doi.org/10.1002/glia.70068
ACS Chem Neurosci. 2025 Jul 24.

ULK1 Knockout Exacerbates Ischemia-Induced Microglial Dysfunction via TRAF6/NF-κB Signaling Pathway.

Ye Xiong, Zhuo Li Li, Xiao Wan Wang, Ting Li, Mai Yin Cui, Min Min Wang, Yan Qiong Fu, Yu Zheng, Wei Wei Xiang, Yang Wang, Bai Hui Chen.

  Activated microglia rapidly migrate to the infarct site, mediate neuroinflammation, and phagocytose cell debris during the acute stage of ischemic stroke; however, the underlying mechanisms remain unclear. In this study, we utilized a cortical photothrombotic ischemic model and found that unc-51-like autophagy activating kinase 1 (ULK1) knockout mice exhibited increased pro-inflammatory microglia, along with upregulated levels of pro-inflammatory mediators. Further studies revealed that ULK1 deletion impaired the phagocytosis of myelin debris by microglia, thereby exacerbating myelin accumulation in the infarct zone and increasing pro-inflammatory phagocytic microglia. Moreover, coimmunoprecipitation results showed that ULK1 bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) in primary microglia. Subsequently, we observed that the protein levels of ULK1 and phosphorylated nuclear factor κ-B (p-NF-κB) were regulated by the administration of the TRAF6 inhibitor C25-140 in ischemic wild-type (WT) mice. Overall, our study suggests that ULK1 regulates microglial activation and neuroinflammation via the TRAF6/NF-κB signaling pathway in ischemic stroke.

Keywords:  TRAF6; ULK1; ischemic stroke; microglia; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.1021/acschemneuro.5c00284
Neuropharmacology. 2025 Jul 21. pii: S0028-3908(25)00299-0. [Epub ahead of print] 110591

Pantothenic acid-mediated inhibition of microglial inflammation via the JAK2/STAT3 pathway enhances motor function recovery after Spinal cord injury.

Yuepeng Fang, Ce Zhang, Zhijie Yang, Xiangrui Zhao, Yongcheng Yin, Zhengxin Jin, Pengchong Zhu, Bin Ning.

  This study employed transcriptome sequencing and targeted metabolomics to delve into the molecular alterations in mouse spinal cords following spinal cord injury (SCI). Notably, a significant depletion of pantothenic acid (PA) was observed in the injured spinal cord, exhibiting an inverse correlation with microglial inflammation and activation. To further elucidate this relationship, experimental interventions using PA were conducted in SCI mouse models. The results demonstrated that PA administration effectively inhibited microglial inflammation via modulation of the JAK2/STAT3 signaling pathway. This inhibition not only mitigated the neuroinflammatory milieu but also fostered an environment conducive to axonal growth and neuronal regeneration. Consequently, SCI mice treated with PA exhibited improved motor function recovery compared to untreated controls. Our findings not only deepen the understanding of the relationship between PA and neuroinflammatory processes in SCI but also highlight the therapeutic potential of PA in promoting neuronal regeneration and functional recovery.

Keywords:  JAK2/STAT3 signaling pathway; Transcriptome sequencing; anti-inflammatory effects; inflammatory cytokines; metabolomic analysis; microglial inflammation; motor function recovery; neuronal regeneration; pantothenic acid; spinal cord injury

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110591
Mol Neurobiol. 2025 Jul 19.

PD-1 Attenuates Neuropathic Pain by Ameliorating NLRP3 Inflammasome-Mediated Microglia Pyroptosis.

Daling Deng, Lulin Ma, Jiwei Shen, Li Huang, Tianhao Zhang, Xinxin Yang, Shiqian Huang, Wenjing Zhao, Yuxi Zhou, Shiwen Fan, Kaixin Wang, Xiangdong Chen.

  Neuropathic pain lacks effective clinical treatments due to its complex pathogenesis. Growing evidence indicates that programmed cell death receptor-1 (PD-1) plays a vital role in reducing neuropathic pain. Recent studies have also implicated the nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing 3 (NLRP3 inflammasome and its associated pyroptosis in the pathophysiology of various pain types. However, it remains unclear whether PD-1 relieves neuropathic pain by regulating NLRP3 inflammasome activation and subsequent pyroptosis. This study found the dynamics of spinal cord PD-1 expression in a spared nerve injury (SNI) model of neuropathic pain. Additionally, SNI markedly increased the activation of the NF-κB pathway, NLRP3 inflammasomes, and pyroptosis in the spinal cord. Intrathecal administration of the PD-1 inhibitor RMP1-14 worsened SNI-induced neuropathic pain and significantly heightened the inflammatory response, NF-κB pathway activation, and NLRP3 inflammasome assembly. Notably, RMP1-14 specifically promoted microglial pyroptosis, with no significant effect on neuronal pyroptosis. Conversely, intrathecal injection of the NLRP3 inhibitor MCC950 alleviated pain hypersensitivity and reduced inflammation. These findings suggest that the analgesic effects of PD-1 are linked to suppression of the NLRP3 inflammasome and its regulation of microglial pyroptosis, highlighting PD-1 as a potential therapeutic target for neuropathic pain.

Keywords:  Inflammation; NLRP3; Neuropathic pain; PD-1

DOI:  https://doi.org/10.1007/s12035-025-05225-5
Am J Pathol. 2025 Jul 18. pii: S0002-9440(25)00240-8. [Epub ahead of print]

AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.

Liang Shao, Ji Zhang, Fan Hu, Wen Chai, Yuxuan Zhou, Pengtao Zou, Ping Zhang.

  Parkinson's disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study is to get better understanding of microglial mitophagy in PD. 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescent (IF) showed that autophagy was enhanced in MPTP-induced PD mice. IF, qRT-PCR, western blot and co-immunoprecipitation (co-IP) also revealed that silencing of Hsp90α protected against mitophagy in PD mice. In microglia/DA neurons co-culture system, ELISA assay, Transmission Electron Microscopy (TEM), JC-1 staining, measurement of ATP content and Annexin V/PI staining showed that lack of Hsp90α in MPTP-treated microglia attenuated DA neuronal death via suppressing mitophagy. IF staining and co-IP confirmed that Hsp90α formed a complex with AHSA1, and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. Hsp90α inhibitor geldanamycin (GA) and AHSA1 knockdown further revealed that AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.

Keywords:  AHSA1; Hsp90α; Parkinson's disease; TOMM70; microglial mitophagy

DOI:  https://doi.org/10.1016/j.ajpath.2025.06.007
Eur J Pharmacol. 2025 Jul 17. pii: S0014-2999(25)00701-0. [Epub ahead of print]1003 177947

Artesunate suppresses ocular inflammation in endotoxin-induced uveitis through inhibiting the NF-κB signaling pathway and M1 macrophage polarization.

Liang Liu, Xiaofeng Hao, Bingwen Lu, Xiaoyu Li, Like Xie.

  Uveitis is an inflammatory eye disease that can lead to visual impairment and blindness, highlighting the need for safer and more effective treatments. This study demonstrates the protective effects of artesunate (ART) and artesunate sustained-release formulation (ARTSR) against endotoxin-induced uveitis (EIU) in rat and rabbit models. In vitro, ART inhibited migration-related genes and reduced migratory ability in lipopolysaccharide (LPS)-stimulated RAW264.7 cells (a murine macrophage cell line). ART effectively suppressed LPS-induced inflammation in BV2 cells (a murine microglial cell line) by modulating microglial polarization and downregulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Notch1 signaling pathways. In EIU rats, ART attenuated clinical inflammation scores, prevented retinal thickening, and reduced inflammatory cell infiltration. ART downregulated pro-inflammatory mediators and M1-related genes, and upregulated M2-related genes in EIU rat eyes, primarily through suppression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. In EIU rabbits, ARTSR reduced protein concentration and cell infiltration in aqueous humor. These findings highlight the therapeutic potential of ART and ARTSR in uveitis by modulating inflammatory responses.

Keywords:  Artesunate; Endotoxin-induced uveitis; Inflammatory responses; Macrophage migration; Microglial polarization; Pro-inflammatory cytokines

DOI:  https://doi.org/10.1016/j.ejphar.2025.177947
Int J Ophthalmol. 2025 ;18(7): 1237-1251

Key immune regulators in retinal ischemia-reperfusion injury via RNA sequencing.

Shan He, Cui-Ying Liu, Chang-Hong Ren, Ting-Ting Meng, Heng Zhao, Xu-Xiang Zhang.

   AIM: To explore the immune cell infiltration and molecular mechanisms of retinal ischemia-reperfusion injury (RIRI) to identify potential therapeutic targets.
METHODS: In the bulk RNA-seq analysis, This study performed differential gene expression analysis, weighted gene co-expression network analysis, and protein-protein interaction network analysis to identify hub genes. QuanTIseq was used to determine the composition of infiltrating immune cells. Following the identification of hub genes, single-cell RNA-seq analysis was employed to pinpoint the specific immune cell types expressing these hub genes. Cell-cell communication analysis to explore signaling pathways and interactions between immune cells was further performed. Finally, the expression of these key immune regulators in vivo using quantitative real-time polymerase chain reaction (qRT-PCR) was validated.
RESULTS: Bulk RNA-seq analysis identified Stat2, Irf7, Irgm1, Igtp, Parp9, Irgm2, Nlrc5, and Tap1 as hub genes, with strong correlations to immune cell infiltration. Single-cell RNA-seq analysis further revealed six immune cell clusters, showing Irf7 predominantly in microglia and Tap1 in dendritic cells (DCs). And cell-cell communication analysis showed that microglia and DCs play central roles in coordinating immune activity. qRT-PCR validated the upregulation of these genes.
CONCLUSION: In the acute phase of RIRI, Irf7 and Tap1 may be the potential therapeutic targets to reduce inflammation and promote neurological function recovery.

Keywords:  RNA sequencing; immune cell infiltration; key immune regulators; retinal ischemia-reperfusion injury; single-cell RNA sequencing

DOI:  https://doi.org/10.18240/ijo.2025.07.06