bims-microg 2026-02-22 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–02–22
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Aurkb deficiency disrupts microglial development, homeostasis and hinders remyelination following cuprizone-induced demyelination.
ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.
Interferon-γ-Responsive Microglia-Derived Extracellular Vesicles Inhibited Neurogenesis After Stroke via MicroRNA-199a-5p/SIRT1 Axis.
Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.
Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.
Neutrophil extracellular traps and microglia/macrophages interactions in stroke: from thromboinflammation to immunotherapy.
Intelligent nanoliposome ameliorate chronic intermittent hypoxia-mediated neuronal injury via a dual regulation microglial inflammation strategy.
Herpes simplex virus-1 induces complement-mediated microglial phagocytosis of synapses in murine primary brain cultures and tissues.
Inhibition of TXNIP/NLRP3/GSDMD Pathway and Antioxidant Therapy Mitigate Cognitive Dysfunction Induced by Chronic Intermittent Hypoxia.
Inflammatory stimulus enhances synaptic material uptake by adult APP microglia in a microfluidic neuron-microglia co-culture model.
Ozone-induced cognitive deficits are mediated by the liver-brain axis: peripheral complement C3 triggers microglial synaptic phagocytosis.
Microglial Lyn Kinase-TRPV4 axis mediates social deficits in a maternal immune activation model.
Anti-CLEC7A nanobody in situ engineering promotes amyloid-β oligomers clearance by CAR-microglia to alleviate Alzheimer's disease pathology in mice.
Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.
NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy.
Neonatal inflammation induces ventral hippocampal microglial priming via epigenetic regulation of BAG3 to enhance adult depression susceptibility in mice.
Astrocyte-microglia crosstalk through Hevin and Toll-like receptor signaling controls developmental thalamocortical synapse refinement.
A Preventable Alzheimer's Disease Microneedle Patch with Synaptic Protection and NLRP3 Inflammasome Suppression in Microglia during Smoking Cessation.

iScience. 2026 Feb 20. 29(2): 114718

Aurkb deficiency disrupts microglial development, homeostasis and hinders remyelination following cuprizone-induced demyelination.

Weixing Yan, Dong Xiang, Li Du, Di Zhu, Qi Jia, Yuting Liu, Siyu Wang, Li Liu, Haihao Guan, Yelin Zhao, Guan Jiang, Sijia Gao, Hui Wang.

  Microglia are crucial for phagocytic clearance of myelin debris, which hinders remyelination and leads to neurological decline during aging and in multiple sclerosis (MS). However, the molecular mechanism enabling microglia to expand and function effectively in remyelination remains elusive. Here, we identified that mitotic kinase Aurkb was upregulated in microglia during early development and in MS. Neonatal deletion of Aurkb disrupted cell density, morphology, and proliferation, which is attributed to stalled mitosis. Inducible Aurkb ablation in adulthood led to microglial dystrophy and disrupted homeostasis. Aurkb deficiency compromised microglial activation in response to LPS-induced inflammation. Critically, Aurkb-deficient mice exhibited accumulated myelin debris and impaired oligodendrocyte regeneration and remyelination in the CPZ-induced demyelination model. Additionally, Aurkb deletion inhibited microglial clearance of myelin debris, independent of reduced microglia numbers. This defect was associated with diminished autophagy. Together, these findings establish Aurkb as a key regulator of microglial development, homeostasis, and responses to remyelination.

Keywords:  Cell biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.114718
Life Sci. 2026 Feb 13. pii: S0024-3205(26)00082-2. [Epub ahead of print]391 124274

ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.

Yi-Chun Chen, Tai-Ju Chiu, Yah-Yuan Wu, Yu-Ting Wang, Kuan-Hsuan Wu, Tu-Hsueh Yeh, Ya-Ju Hsieh, Wan-Shia Chen, Ching-Chi Chiu.

   AIMS: TOMM40 (translocase of outer mitochondrial membrane 40) is crucial for mitochondrial protein import. Mutations in TOMM40 increase the risk of Alzheimer's disease (AD) and trigger neuroinflammation. ALDH2 (aldehyde dehydrogenase 2) has neuroprotective effects, but the therapeutic role of ALDH2 activation in targeting neuroinflammation-induced AD remains unclear.
MATERIALS AND METHODS: In this study, it was hypothesized that TOMM40 mutations cause BV2 microglial activation and neuronal loss by impairing mitochondrial functions and that ALDH2 activation by small-molecule activator Alda-1 exerts anti-neuroinflammatory effect on HT22 hippocampal neurons.
KEY FINDINGS: Expression of mutant TOMM40 (F113L or F131L) induced BV2 microglial activation, reduced ALDH2 activity, and impaired mitochondrial function in BV2 microglia. ALDH2 activation by Alad-1 attenuated mutant TOMM40-induced microglial activation, mitochondrial dysfunction, ROS production, and lipid droplet accumulation. Alda-1 also suppressed mutant TOMM40-induced ROS/NF-κB/NLRP3 inflammasome axis and reduced the secretion of IL-1β, IL-6, and TNF-α. Conditioned medium from mutant TOMM40-expressing microglia induced apoptosis, neurite degeneration, and neuronal death in HT22 hippocampal neurons, which were alleviated by Alda-1 treatment.
SIGNIFICANCE: These findings suggest that ALDH2 activation prevents neuroinflammation-induced hippocampal neuronal death by downregulating NLRP3 inflammasome pathway, reducing lipid droplet accumulation, and enhancing mitochondrial function and neurite outgrowth.

Keywords:  ALDH2; Alda-1; Alzheimer's disease; Lipid droplet; Microglia; NLRP3; Neuroinflammation; TOMM40

DOI:  https://doi.org/10.1016/j.lfs.2026.124274
J Am Heart Assoc. 2026 Feb 20. e043532

Interferon-γ-Responsive Microglia-Derived Extracellular Vesicles Inhibited Neurogenesis After Stroke via MicroRNA-199a-5p/SIRT1 Axis.

Tongtong Xu, Dongliang Qian, Shiyu Deng, Yiyan Guo, Hanlai Li, Yanqin Geng, Lin Gan, Qianyuan Lian, Jingjing Xu, Huaitong Yao, Jing Ye, Enkhbat Myagmartsend, Wanlu Li, Zhijun Zhang, Guo-Yuan Yang, Jixian Wang, Yaohui Tang, Qingzhu An.

   BACKGROUND: Previous studies have reported the presence of interferon-responsive microglia in the brain after central nervous system injury. However, their roles and the underlying mechanisms in neurological function recovery remain poorly understood.
METHODS: Adult male mice were subjected to 90-minute transient middle cerebral artery occlusion, and brain tissues were analyzed using single-cell RNA sequencing (scRNA-seq) at 14 days after stroke. Immunostaining, quantitative real-time polymerase chain reaction and ELISA were conducted to validate the presence of interferon-γ-responsive microglia in stroke mice brains. Extracellular vesicles (EVs) were isolated from interferon-γ-treated BV2 microglia via ultracentrifugation. Interferon-γ EVs were then used to treat neural stem cells (NSCs) in vitro or administered intravenously to mice every other day, starting at 7 days after transient middle cerebral artery occlusion. Neurobehavioral tests, cresyl violet staining, Golgi staining, and immunostaining were performed to evaluate NSC differentiation, neurogenesis, and neurobehavioral recovery. Micro RNA (miR) sequencing and bioinformatic analysis were conducted to explore targeted genes and signaling pathways underlying interferon-γ EV-mediated inhibition of neurogenesis.
RESULTS: Single-cell RNA sequencing, immunostaining, quantitative real-time polymerase chain reaction, and ELISA showed the presence of interferon-γ-responsive microglia in stroke mice brains. Interferon-γ EVs were internalized by NSCs, leading to reduced NSC survival and neuronal differentiation. Administration of interferon-γ EVs increased brain atrophy volume, inhibited neurobehavioral recovery and neurogenesis in mice after stroke. miRNA array revealed 12 upregulated microRNAs, and treatment with miR-199a-5p mimic inhibited the survival and neuronal differentiation of NSCs, and knockdown of miR-199a-5p in interferon-γ EVs increased neurogenesis in stroke mice. miRNA database analysis and luciferase reporter assay identified SIRT1 as a downstream target gene of miR-199a-5p. Treatment with SIRT1 agonist promoted the survival and neuronal differentiation of NSCs, confirming that interferon-γ EVs inhibited neurogenesis via miR-199a-5p/SIRT1.
CONCLUSIONS: Our study demonstrated that interferon-γ EVs inhibited the survival and neuronal differentiation of NSCs, exacerbating brain injury via the miR-199a-5p/SIRT1 axis after ischemic stroke, providing a novel target for treating ischemic stroke.

Keywords:  extracellular vesicles; interferon‐γ–responsive microglia; neurogenesis; stroke

DOI:  https://doi.org/10.1161/JAHA.125.043532
Free Radic Biol Med. 2026 Feb 13. pii: S0891-5849(26)00130-9. [Epub ahead of print]247 448-468

Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.

Zhongmin Fan, Lixia Du, Lu Yin, Hao Liu, Mengyun Li, Jing Li, Fuhong Liu, Lin Yang, Jin Li, Qi Wang, You Wu, Hongwei Ma, Xijing Zhang.

Transient receptor potential vanilloid 1 (TRPV1), a canonical non-selective cation channel predominantly expressed on the cellular membrane of peripheral sensory neurons, is responsible for perceiving physical and chemical stimuli. Accumulating evidence indicates TRPV1 expression in the central nervous system, the role of which remains elusive. Here, we demonstrate that, distinct from neurons or astrocytes, TRPV1 is distributed on the mitochondrial membrane of microglia in the hippocampus, mediating neurotoxic microglial responses during both acute and convalescent stages of sepsis by disrupting mitochondrial dynamics. During the pathogenesis of sepsis-associated encephalopathy (SAE), hippocampal microglia exhibit elevated TRPV1 expression concurrent with a pro-inflammatory state. Genetic ablation of TRPV1 or application of TRPV1 antagonist attenuates microglial inflammatory polarization and phagocytic dysfunction both in vivo and in vitro. This mitigates immoderate neuroinflammation and aberrant synaptic pruning, thereby reshaping synaptic plasticity and ameliorating cognitive deficits in SAE. Mechanistically, TRPV1 reprograms microglial phenotype with dysregulated capability for glycometabolism by affecting their mitochondrial function. Following LPS challenge, TRPV1 activation exacerbates mitochondrial damage and impairs ATP production in microglia, resulting in bioenergetic failure and excessive generation of mitochondrial reactive oxygen species (mtROS) and mtDNA. Conversely, TRPV1 depletion enhances oxidative phosphorylation capacity of microglia to counteract LPS toxicity. TRPV1 silencing further promotes the formation of cristae-deficient mitochondria, sustaining reductive proline biosynthesis and shifting microglia toward a protective pattern. Collectively, our findings suggest that TRPV1 compromises the metabolic reprogramming of microglia by perturbing mitochondrial dynamics, revealing a novel therapeutic target for SAE intervention.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.02.033
J Headache Pain. 2026 Feb 20.

Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.

Junjie Li, Zhilun Yang, Xiaojuan Mi, Qiang Wang, Juan Ding, Ziqi Feng, Xia Ma, Liping Zhang, Juan Liu.



Keywords:  AKT serine/threonine kinase 2; Cognitive impairment; Microglia activation; Neuroinflammation; Nuclear receptor subfamily 4 group a member 1; Trigeminal neuralgia

DOI:  https://doi.org/10.1186/s10194-026-02293-3
Front Immunol. 2026 ;17 1752471

Neutrophil extracellular traps and microglia/macrophages interactions in stroke: from thromboinflammation to immunotherapy.

Nurittin Ardic, Rasit Dinc.

  Stroke remains a leading cause of death and disability worldwide, and inflammation is increasingly recognized as a key driver of acute injury and secondary neurodegeneration. Among post-stroke immune mediators, neutrophil extracellular traps (NETs) have emerged as critical amplifiers of thromboinflammation and cerebrovascular injury. Parallel developments highlight microglia and infiltrating macrophages as key regulators of sterile inflammation in ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). However, the bidirectional interaction between NETs and microglia/macrophages has not been comprehensively analyzed despite its translational importance. This review describes the mechanistic pathways by which NET components activate microglial pattern recognition receptors, triggering inflammasome activation, inflammatory signaling cascades, and cytokine release. Activated microglia, in turn, promote neutrophil recruitment and NETosis, creating a self-reinforcing cycle. Evidence from ischemic and hemorrhagic stroke demonstrates how NET-microglia interactions lead to neurovascular complications such as blood-brain barrier disruption, microvascular dysfunction, and neuronal injury. We examine therapeutic strategies targeting NET formation and destruction, microglial modulation, and combination approaches to interrupt this inflammatory axis. We highlight novel biomarker and imaging approaches that may enable personalized immunotherapy. Together, these strategies position the NET-microglia/macrophage axis as a promising immunomodulatory target in ischemic and hemorrhagic stroke, offering new avenues for precision therapy development.

Keywords:  immunotherapy; microglia/macrophages; neutrophil extracellular traps (NETs); stroke; thromboinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1752471
Mater Today Bio. 2026 Apr;37 102865

Intelligent nanoliposome ameliorate chronic intermittent hypoxia-mediated neuronal injury via a dual regulation microglial inflammation strategy.

Hongwei Wang, Xu Wang, Yun Zhu, Zhiyuan Niu, Xiwen Ou, Weiyu Zhang, Shuting Zhuang, Yun Ke, Fan Yang, Mingliang Pei, Song Liu.

  The etiology of obstructive sleep apnea syndrome (OSAS)-associated cognitive dysfunction is unclear and complex. There is growing evidence demonstrate that hyper-activated neuroinflammation, M1 phenotypic microglia polarization, and subsequent neuronal inflammatory damage induced by chronic intermittent hypoxia (CIH) pose a crucial role in OSAS-related cognitive dysfunction. However, the regulatory mechanisms remain unclear, and during treatment, there are inevitable issues with small molecule drugs such as hydrophobicity, lack of targeting, and uncontrolled dosages, especially their inability to cross the blood-brain barrier (BBB), which severely hinders the treatment of CIH related cognitive dysfunction. Herein, a "dual regulation" microglial inflammation strategy was proposed using intelligent nanoliposomes (Ang-Lip@BAY/GW1929), capable of simultaneously regulating PPARγ signaling and IκBα/p65 pathway to reverse the inflammatory microglia transformation. The cationic Ang-Lip@BAY/GW1929 was innovatively used for the dual-targeted identification of CIH-activated microglia that highly express LRP-1 and carry a negative surface charge, to achieve efficient delivery and release of drugs. Simultaneously, PPARγ agonist (GW1929), and IκBα phosphorylation inhibitor (BAY) were delivered from ROS-responsive Ang-Lip@BAY/GW1929 to coordinate the inhibition of NF-κB pathway through PPARγ and IκBα/p65 signaling to systemically regulate microglial polarization, neuroinflammation, neuronal damage, and cognitive dysfunction. Collectively, the study proposed strategies for building bio-targeted liposome-based nanovector to relieve CIH-induced neuron injury, and systematically described treatment mechanisms on CIH related impairment, opening a new path for the treatment of CIH related cognitive dysfunction.

Keywords:  Intermittent hypoxia; Microglia; NF-κB pathway; Nanoliposome; Neuronal injury

DOI:  https://doi.org/10.1016/j.mtbio.2026.102865
Cell Commun Signal. 2026 Feb 20.

Herpes simplex virus-1 induces complement-mediated microglial phagocytosis of synapses in murine primary brain cultures and tissues.

Mariya Timotey Miteva, Virginia Protto, Francesco Zanzi, Francesco Pastore, Chiara Simone, Cristian Ripoli, Maria Elena Marcocci, Roberto Piacentini, Claudio Grassi, Anna Teresa Palamara, Giovanna De Chiara.

   BACKGROUND: Numerous studies suggest that abnormal upregulation of the complement cascade, a key component of the innate immune system, is involved in the pathogenesis of Alzheimer's disease (AD), also contributing to synapse elimination in the brain. Several pieces of evidence suggest that recurrent herpes simplex virus-1 (HSV-1) infection reaching the brain is one of the AD risk factors, including those reporting synaptic loss and consequent cognitive deficit following multiple virus replication in the brain. However, the role of complement cascade activation in such events remains unexplored.
METHODS: Murine primary neurons co-cultured or not with microglial BV2 cells and organotypic hippocampal brain slices were used as experimental models of HSV-1 infection. Virus effects on complement cascade activation and synaptic loss were assessed by evaluation of protein and mRNA levels of specific complement components and synaptic markers. Confocal immunofluorescence microscopy was used to analyze microglial phagocytosis of synapses. To evaluate the role of complement cascade activation in such event, experimental models were treated with a neutralizing anti-C3 antibody within the infection. Two-photon imaging and patch-clamp recordings of organotypic hippocampal slices were used to quantify dendritic spine density on secondary apical dendrites of CA1 pyramidal neurons and synaptic transmission.
RESULTS: We first found that HSV-1 infection significantly upregulates the expression of components of the classical complement cascade at both mRNA and protein levels, and promotes their localization at synapses. Then, we provide evidence that HSV-1 infection causes increased microglial phagocytosis of synapses, which is partially prevented when the complement cascade is inhibited. Furthermore, by exploiting murine organotypic hippocampal slices, we confirmed that the virus triggers synaptic damage through microglial pruning of synapses via a complement-dependent mechanism. Importantly, in infected CA1 neurons, we detected a significant decrease in spine density, which was paralleled by functional alterations in synaptic transmission. Both events were rescued when infection is performed in the presence of an antibody neutralizing the complement C3 protein.
CONCLUSION: Our data indicate that HSV-1 infection triggers aberrant complement activation and complement-mediated microglial engulfment of damaged synapses, further supporting the role of HSV-1 in neurodegeneration.

Keywords:  Alzheimer’s disease; Complement proteins; HHV-1; HSV-1; Herpes simplex virus; Microglial synaptic pruning; Neurodegeneration

DOI:  https://doi.org/10.1186/s12964-026-02745-y
Antioxid Redox Signal. 2026 Feb;44(7-9): 373-392

Inhibition of TXNIP/NLRP3/GSDMD Pathway and Antioxidant Therapy Mitigate Cognitive Dysfunction Induced by Chronic Intermittent Hypoxia.

Hongwei Wang, Xu Wang, Xiwen Ou, Weiyu Zhang, Lin Song, Song Liu.

   AIMS: Mitochondrial homeostasis is essential for maintaining central nervous system function. Both inflammation and oxidative stress induced by chronic intermittent hypoxia (CIH) can result in neuronal mitochondrial injury in obstructive sleep apnea syndrome (OSAS)-related cognitive dysfunction. Recent evidence implicates neuronal impairment caused by abnormal activation of microglia as a key contributor to CIH-induced cognitive dysfunction. However, the mechanism between microglia and neuronal injury remains elusive. This study seeks to elucidate the underlying mechanism of microglia-mediated neuronal injury in CIH-induced cognitive dysfunction.
RESULTS: Both the levels of pro-inflammatory factors and reactive oxygen species (ROS) were elevated; neuronal mitochondrial and cytomembrane injury and neuronal pyroptosis also occurred in CIH models in vitro and in vivo. Microglial cells RNA sequencing data revealed that CIH upregulated the nucleotide-binding and oligomerization domain-like receptor pathway, and in vitro experiments confirmed that the thioredoxin-interacting protein (TXNIP)/nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) pathway modulated inflammation and oxidative stress in BV-2 cells and regulated neuronal mitochondrial and cytomembrane injury and pyroptosis. Co-immunoprecipitation results verified that TXNIP bound directly to NLRP3 in BV-2 cells. Furthermore, GSDMD-derived inhibitor (Ac-FLTD-CMK) abolished the elevation in inflammation and oxidative stress markers induced by TXNIP overexpression after CIH exposure. In addition, it alleviated HT-22 cells' mitochondrial and cytomembrane injury and suppressed the activation of TXNIP/NLRP3/GSDMD pathway in BV-2 cells induced by CIH after the application of mitochondrial antioxidant Mito-TEMPO to BV-2 cells, thereby mitigating microglia-mediated neuronal pyroptosis. These findings were corroborated by in vivo experiments.
INNOVATION AND CONCLUSION: These results reveal that microglial TXNIP/NLRP3/GSDMD pathway activation is a key mechanism linking CIH to neuronal injury in OSAS-related cognitive dysfunction. Inhibition of TXNIP/NLRP3/GSDMD pathway and antioxidant therapy could protect against CIH-induced cognitive dysfunction by ameliorating the damaging effects of cytokines of inflammation and oxidative stress from microglia, while preventing neuronal mitochondrial and cytomembrane injury and pyroptosis. This work identifies a promising target for pharmacological intervention in OSAS-related cognitive dysfunction. Antioxid. Redox Signal. 44, 373-392.

Keywords:  Chronic intermittent hypoxia; cognitive dysfunction; microglia; neuronal injury

DOI:  https://doi.org/10.1177/15230864251406615
J Neuroinflammation. 2026 Feb 19.

Inflammatory stimulus enhances synaptic material uptake by adult APP microglia in a microfluidic neuron-microglia co-culture model.

Dolores Siedlecki-Wullich, Anne-Marie Ayral, Lukas Iohan, Célia Lemeu, Valérie Buiche, Karine Blary, Julien Chapuis, Fanny Eysert, Delphine Beury, Myriam Delacre, David Hot, Takahiro Masuda, Klaus-Peter Knobeloch, Marco Prinz, Jean-Charles Lambert, Devrim Kilinc.



Keywords:  APP mouse model; Alzheimer’s disease; IL-1β; PSD95; microfluidics; microglia; neuroinflammation; synapse

DOI:  https://doi.org/10.1186/s12974-026-03748-9
J Neuroinflammation. 2026 Feb 19.

Ozone-induced cognitive deficits are mediated by the liver-brain axis: peripheral complement C3 triggers microglial synaptic phagocytosis.

Yougang Wang, Haomin Qi, Weiran Dong, Yushan Chen, Desiré Nisubire, Yan Zeng, Jinquan Li.

  Ozone (O3) is a significant global air pollutant. Recent epidemiological studies have established a correlation between O3 exposure and an increased risk of neurological disorders. However, the underlying mechanisms by which O3 induces cognitive deficits remain unclear. This study demonstrated that exposure to environmentally relevant O3 levels resulted in significant cognitive impairment in mice. These deficits arose from hippocampal synaptic injury, characterized by reduced dendritic spine density, disrupted synaptic ultrastructure, and impaired long-term potentiation. Mechanistically, O3 activated the liver complement pathway, leading to increased levels of complement component 3 (C3) and its subsequent release into the bloodstream. Furthermore, O3 compromised the integrity of the blood-brain barrier, allowing peripheral C3 to infiltrate the hippocampus. Notably, C3 served as a key signal that triggered local pro-inflammatory microglial activation and enhanced their phagocytosis of excitatory synapses, ultimately resulting in synaptic loss and cognitive decline. Importantly, both the microglial inhibitor minocycline and liver-specific C3 knockdown suppressed pro-inflammatory microglial activation and restored synaptic plasticity and cognitive function. These findings systematically reveal a novel liver-brain axis in O3 neurotoxicity, whereby peripheral C3 drives central microglial phagocytosis of excitatory synapses, offering new mechanistic insights and potential therapeutic targets for O3-related neurological diseases.

Keywords:  Ozone; cognitive impairment; complement C3; liver–brain axis; microglia

DOI:  https://doi.org/10.1186/s12974-026-03746-x
J Neuroinflammation. 2026 Feb 19.

Microglial Lyn Kinase-TRPV4 axis mediates social deficits in a maternal immune activation model.

Rezwanul Islam, Feng Zhang, Hadi Hasan Choudhary, Jun Yoshida, Ajith J Thomas, Ben Sorum, Khalid A Hanafy.



Keywords:  Autism; Calcium imaging; Lyn kinase; MIA; Microglia; Social deficits; TRPV4

DOI:  https://doi.org/10.1186/s12974-026-03738-x
J Control Release. 2026 Feb 15. pii: S0168-3659(26)00112-4. [Epub ahead of print] 114710

Anti-CLEC7A nanobody in situ engineering promotes amyloid-β oligomers clearance by CAR-microglia to alleviate Alzheimer's disease pathology in mice.

Chongzheng Yan, Zhichao Kong, Yuxue Pan, Zhipeng Fu, Kun Han, Xiaotian Zhao, Jing Zhang, Longyu Bo, Weiyi Sun, Jinxin Gao, Xianghui Dong, Zuolin Zheng, Xiao Yue, Peng Sun, Xinyi Jiang, Chen Chen.

  Chimeric antigen receptor microglia (CAR-M)-mediated amyloid-β oligomers (AβO) phagocytosis shows great promise in Alzheimer's disease (AD) treatment, however, the limited AβO degradation of CAR-M compromises their anti-AβO potency. This work here reports an in situ engineered agonistic anti-C-type lectin domain containing 7 A (CLEC7A) nanobody to accelerate AβO degradation of CAR-M, augmenting their anti-AβO efficacy. Specifically, with the intranasal-delivered microglia-targeting lipid nanoparticles (LNP), this work generates an AβO-specific degradation-potentiated CAR-M by introducing dual mRNAs encoding AβO-specific CAR and anti-CLEC7A nanobody into the cerebral microglia. These data show that these engineered CAR-M exhibited superior phagocytic function and promoted intracellular AβO degradation via activating CLEC7A-spleen tyrosine kinase (SYK) signaling pathway through the local secretion of anti-CLEC7A nanobody. In the APP/PS1 mouse model of AD, these in situ reprogrammed CAR-M significantly reduced cerebral Aβ levels, suppressed neuroinflammation, and restored cognitive function. In sum, these findings demonstrate that potentiating AβO degradation within CAR-M effectively alleviates AD pathology, providing a promising therapeutic strategy for AD with broad application in other neurodegenerative diseases.

Keywords:  Alzheimer's disease; Amyloid-β oligomers; Anti-CLEC7A nanobody; Chimeric antigen receptor microglia; Lipid nanoparticle

DOI:  https://doi.org/10.1016/j.jconrel.2026.114710
Sci Signal. 2026 Feb 17. 19(925): eady8398

Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.

Kaitlyn E DeMeulenaere, Rogan A Grant, Megan E Martin, Hiam A Valencia, Jelena Radulovic, Michael W Salter, Murali Prakriya.

Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca2+ signaling in regulating broader microglial cell state transitions and identified Orai1 Ca2+ channels as critical regulators of microglial plasticity and neuroinflammatory signaling. Conditional deletion of Orai1 in microglia impaired their ability to adopt reactive, proinflammatory states. Transcriptomic and metabolomic profiling revealed that Orai1 deletion suppressed the expression of proinflammatory genes linked to immunity, inflammation, and cell metabolism. Conversely, Orai1-deficient microglia generated greater amounts of neuroprotective and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite itaconate. In a model of CNS inflammation induced by peripheral lipopolysaccharide (LPS) challenge, microglial Orai1 deletion attenuated microglial and astrocyte reactivity and reduced hippocampal amounts of the proinflammatory cytokines IL-1β and IL-6. Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced decreases in motivational behaviors, including impaired reward-seeking and escape behaviors. These findings establish Orai1 channels as key regulators of microglial cell state transitions, linking Ca2+ signaling to neuroinflammation and inflammation-driven behavioral dysfunction.

DOI: https://doi.org/10.1126/scisignal.ady8398
Brain Behav Immun. 2026 Feb 17. pii: S0889-1591(26)00240-0. [Epub ahead of print] 106492

NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy.

Qing-Ru Wu, Dong-Dong Zhu, Hao-Ze Wang, Jing Tian, Xin-Yuan Chen, Yun-Le Li, Xiao-Yu Ruan, Xiao-Ying Bi, Yan Gu, Hai-Ling Zhang.

  Microglia are critical in the neuroinflammatory cascade of sepsis-associated encephalopathy (SAE), yet their functional heterogeneity and transcriptional regulators remain poorly characterized. Here, through single-cell RNA sequencing (scRNA-seq) of murine brains post-cecal ligation and puncture (CLP)-induced sepsis, we resolved six microglial clusters. Notably, a subset of inflammasome-activated microglia emerged as a driver for neuroinflammation and cognitive impairment, with marked upregulation of Nlrp3, Il1b, Tnf and enriched pathways for interleukin-1β (IL-1β) production and neuron death. Transcriptional profiling of the cluster highlighted nucleoside diphosphate kinase 2 (NME2) as a marker transcription factor, with its expression and nuclear localization dynamically upregulated post-CLP. Mechanistically, NME2 directly bound the Nlrp3 promoter and recruited enhancer of polycomb homolog 2 (EPC2), a component of the NuA4 histone acetyltransferase complex, to induce H2AK5 acetylation and chromatin remodeling, thereby enhancing Nlrp3 transcription. Conditional knockout of Nme2 in microglia or pharmacological inhibition using stauprimide significantly decreased cerebrospinal fluid IL-1β, attenuated neuronal cell death, and rescued both working memory and recognition memory in septic mice. These findings identify NME2 as a critical transcription regulator of inflammasome-activated microglial lineage dynamics through epigenetic control of NLRP3, offering a mechanistic rationale for targeting the NME2-EPC2 axis to mitigate sepsis-induced cognitive impairment.

Keywords:  Histone acetylation; Inflammasome; Microglia; NLRP3; NME2; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.bbi.2026.106492
Brain Behav Immun. 2026 Feb 16. pii: S0889-1591(26)00242-4. [Epub ahead of print]135 106494

Neonatal inflammation induces ventral hippocampal microglial priming via epigenetic regulation of BAG3 to enhance adult depression susceptibility in mice.

Yang Yang, Jing Rong, Yujie Zhang, Yichao Zhu, Xiaoli Wang, Sha Sha, Jun Yao, Jun Du, Rong Zhou.

   BACKGROUND: Neonatal inflammation increases the risk of adult depression, but the mechanisms remain unclear. Under the two-hit hypothesis, early-life inflammation may enhance vulnerability to later-life stress. Whether neonatal inflammation induces depression susceptibility via microglial priming, and the molecular basis of this process, remain unknown.
METHODS: Neonatal mice (postnatal day 4) received intraperitoneal injections of lipopolysaccharide (LPS; 10, 50, or 100 μg/kg) or saline. In adulthood, mice were exposed to a subthreshold 2-week chronic unpredictable mild stress (CUMS) paradigm. Depression-like behaviors, microglial priming, molecular alterations, and DNA methylation were assessed. Genetic (Bag3 knockout) and pharmacological (minocycline; S-adenosylmethionine, SAM) interventions were applied.
RESULTS: Neonatal exposure to a moderate dose of LPS (50 μg/kg), but not lower or higher doses, selectively increased susceptibility to adult depression-like behaviors and induced microglial priming in the ventral hippocampus (vHPC). Subthreshold CUMS alone failed to induce microglial activation or depressive phenotypes, but robustly activated primed vHPC microglia, triggered neuroinflammation, and precipitated depressive-like behaviors in neonatally LPS-exposed mice; these effects were fully reversed by minocycline. Neonatal moderate LPS induced sustained BAG3 upregulation in the vHPC. Genetic deletion of Bag3 abolished microglial priming and depression susceptibility. At the epigenetic level, neonatal moderate LPS caused persistent hypomethylation of the Bag3 promoter, which was reversed by SAM supplementation.
CONCLUSION: Moderate neonatal inflammation establishes a BAG3-dependent microglial primed state in the vHPC via persistent epigenetic remodeling, thereby enhancing vulnerability to adult stress-induced depression. These findings identify BAG3-centered epigenetic-microglial crosstalk as a critical mechanistic hub linking early-life inflammation to later depression susceptibility.

Keywords:  BAG3; DNA methylation; Depressive susceptibility; Microglia priming; Neonatal inflammation; Neuroinflammation; Ventral hippocampus

DOI:  https://doi.org/10.1016/j.bbi.2026.106494
Neuron. 2026 Feb 19. pii: S0896-6273(25)00984-5. [Epub ahead of print]

Astrocyte-microglia crosstalk through Hevin and Toll-like receptor signaling controls developmental thalamocortical synapse refinement.

Juan J Ramirez, Evelyn J Hardin, Kristina Sakers, Jinhu Kim, Crystal Colón Ortiz, Justin T Savage, Richa Hanamsagar, Carina L Block, Sandeep K Singh, Staci D Bilbo, Cagla Eroglu.

  Synapse formation and elimination are two crucial processes that occur concurrently in the developing brain. Astrocytes and microglia control both processes, yet how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination is unknown. Astrocytes secrete the synaptogenic protein Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Here, we found that, in addition to this synaptogenic function, Hevin directly signals to microglia by interacting with Toll-like receptor 4 (TLR4). This signaling occurs when Hevin is proteolytically cleaved, producing a C-terminal fragment that is no longer synaptogenic. We found that Hevin, through TLR4, induces a distinct microglial state defined by increased TLR2 expression and phago-lysosomal content in vitro and in vivo. Microglial TLR4 signaling is required for the proper elimination of thalamocortical synapses during early postnatal development.

Keywords:  Hevin/Sparcl1; TLR4; astrocyte; microglia; thalamocortical synapse

DOI:  https://doi.org/10.1016/j.neuron.2025.12.028
ACS Nano. 2026 Feb 16.

A Preventable Alzheimer's Disease Microneedle Patch with Synaptic Protection and NLRP3 Inflammasome Suppression in Microglia during Smoking Cessation.

Huangjuan Li, Meihua Li, Chenglin Li, Dongdong Liu, Yuzhen Kang, Yingqi Tang, Peijian Feng, Chenggen Qian.

  Long-term smoking elevates the risk of Alzheimer's disease (AD), yet it is overlooked that nicotine replacement therapy (NRT) inadvertently exacerbates tau pathology during smoking cessation. Here, we mimicked the nicotine replacement patch to design a microneedle patch for the prevention of Alzheimer's disease (PADM), capable of regulating microglia with synaptic protection and NLRP3 inflammasome suppression during smoking cessation. We first demonstrated that nicotine (NIC) transiently preserved synaptic integrity by upregulating the "do not eat me" signal SIRPα on microglia, reducing aberrant synaptic pruning and enhancing amyloid-β (Aβ) clearance in early AD. However, the NLRP3 inflammasome of microglia was activated after NIC intervention and exhibited tau hyperphosphorylation in neurons in late pathology of AD. To address this, we further integrated a natural NLRP3 inhibitor, resveratrol (RES), with NIC into a bilayer microneedle patch. The tip layer enabled sustained low-dose NIC release for smoking cessation, while the backing gel reservoir slowly released RES to suppress neuroinflammation. In APP/PS1 mice, early smoking cessation intervention improves cognition and reduces Aβ burden, and continuous RES delivery prevented late-stage tau pathology. The PADM patch offers a safe prophylactic approach to AD during smoking cessation in high-risk populations.

Keywords:  Alzheimer’s disease; amyloid-β; drug delivery; microglia; microneedle

DOI:  https://doi.org/10.1021/acsnano.6c00812