bims-microg 2026-04-19 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–04–19
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice.
Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy.
A reciprocal glial circuit calibrates injury information and governs the tissue response balance.
Prmt6 Deficiency or Inhibition Restores Microglial Homeostasis and Promotes Scar-Limited Repair in Adult Spinal Cord Injury.
Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.
Host-directed nanotherapy for the treatment and imaging of tuberculous meningitis.
Platelet factors 4 produces an antidepressant effect in mice via inhibition of neuroinflammation.
Promoting donor microglial replacement through augmented conditioning or radiation sensitivity.
Microglia respond to and induce anxiety and grooming in mice using calcium signaling.
Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.
Trem2 exacerbates ischemic brain injury through Gpnmb in a photothrombotic stroke model.
Neonatal sevoflurane exposure disrupts the lung-brain axis and drives microglial neuroinflammation and cognitive deficits.
Type 2 Diabetes Promotes the Microglial Pyroptosis by Activating NLRP3 Inflammasome to Impede Remyelination After Spinal Cord Injury.
An engineered ROS-responsive cascade nanoplatform delays Alzheimer's disease progression via Nrf2/GPX4-mediated microglial functional reprogramming.
Bindarit attenuates brain injury and neuroinflammation in status epilepticus by disrupting C3/C3aR signaling and modulating microglia-astrocyte interactions.
Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.
Activated microglia contribute to paraquat neurotoxicity through neuroinflammation and regulation of phenotypic polarization of astrocytes.
TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.
Functional genomic profiling of schizophrenia-associated genes reveals key microglial regulators.
Therapeutic potential of concentrated growth factor for spinal cord injury: Targeting microglial polarization and inflammation regulation.

Nat Commun. 2026 Apr 17.

Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice.

Shumin Gao, Qingxiu Lin, Xiaotong Liu, Meixiang Jia, An-Yi Zhang, Zhendong Feng, Lei Han, Nianzhuang Qiu, Xiao-Xing Liu, Huajie Zhai, Haizhen Zhang, Jing Zhang, Xiaodan Ding, Yan Zhang, Lin Lu, Jie Shi, Jia Jia Liu, Ya Bin Wei.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive behaviors. Recent studies have indicated that heterozygous mutations in the mixed lineage leukemia 5 (MLL5) gene are implicated in ASD susceptibility and associated with neurodevelopmental abnormalities. However, the detailed mechanisms remain unclear. Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors. We also show that Mll5 acts as an epigenetic regulator, modulating microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which is associated with deficient glucose metabolism. Furthermore, microglia derived from individual with ASD exhibit parallel reductions in MLL5 expression and phagocytic function. By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in Mll5 haploinsufficienct mice. Our findings highlight MLL5's critical role in ASD and its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-71922-x
Nat Commun. 2026 Apr 15.

Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy.

Rasmus Rydbirk, Frederik Nørby Friis Sørensen, Jonas Folke, Henriette Haukedal, Andrea Asenjo Martinez, Irene Lisa Vargas, Simone McGarry, Oline Chantell Hollmann, Camila Gherardelli, Sofia Sepulveda, Adam T Szafran, Michael A Mancini, Sanne Simone Kaalund, Tomasz Brudek, Lisette Salvesen, Sara Bech, Justyna Okarmus, Peter Kharchenko, Morten Meyer, Claudio Soto, Kristine Freude, Abhisek Mukherjee, Susana Aznar, Konstantin Khodosevich.

Multiple system atrophy (MSA) is a rare, age-related neurodegenerative disease that shares clinical and pathological features with Parkinson's disease (PD) but presents a more devastating disease course. To elucidate the distinct cellular pathophysiology, we performed single-nucleus RNA sequencing on postmortem striatal brain tissue from 7 MSA and 12 PD patients, and 10 non-neurological cases. Here, we show significant compositional differences in astroglia and microglia subtypes, while oligodendroglia and neurons are comparable. PD brains show abundant microglia expressing MHC class II HLA haplotypes, indicative of a proinflammatory state, alongside more homeostatic astrocytes. In contrast, MSA lack activated microglia but has more reactive astrocytes compared to PD. Transcriptomic analysis suggests compromised oligodendrocyte signaling in MSA, with microglia being in a state of immune tolerance or exhaustion. Microglia derived from iPSC exposed to patient cerebrospinal fluid exhibit reduced phagocytic activity, especially in MSA. These findings underscore a dysfunctional immune response in MSA as a potential contributor to the more severe pathophysiology of MSA.

DOI: https://doi.org/10.1038/s41467-026-71525-6
Neuron. 2026 Apr 15. pii: S0896-6273(26)00222-9. [Epub ahead of print]

A reciprocal glial circuit calibrates injury information and governs the tissue response balance.

Pengwei Luan, Jianming Jia, Yue Chen, Fengxue Xi, Anett D Schwarcz, Xiujie Jiang, Zsuzsanna Környei, Balázs Kalmár, Ya Wang, Ádám Dénes, Miao Jing.

  Brain injury elicits complex tissue responses that are dynamically regulated between activation and resolution, yet the mechanisms that govern this balance remain elusive. We show that acute injury evokes focal extracellular ATP events (Inflares) with characteristic spatiotemporal signatures that scale quantitatively with injury severity, suggesting a glial mechanism for damage calibration. We further reveal that microglia exert negative feedback on Inflares by tuning interleukin (IL)-1β output based on extracellular ATP levels and cellular state. The IL-1β signal is directly received by astrocytes through IL-1R1 and intracellular Ca2+-calcineurin signaling, where it converges with injury input to shape Panx1-dependent ATP release. These bidirectional interactions form a reciprocal glial circuit that enforces a balanced injury response, while disrupting the circuit destabilizes the dynamic control, impairing the cellular reactivity and worsening early injury outcomes. Our findings uncover a glial circuit and molecular players that dynamically regulate tissue injury responses.

Keywords:  ATP Inflare; IL-1β; astrocyte; brain injury; feedback control; glial circuit; microglia; purinergic signaling

DOI:  https://doi.org/10.1016/j.neuron.2026.03.031
Adv Sci (Weinh). 2026 Apr 17. e75325

Prmt6 Deficiency or Inhibition Restores Microglial Homeostasis and Promotes Scar-Limited Repair in Adult Spinal Cord Injury.

Weilin Peng, Zhengqiang Wu, Yu Xiong, Zhongya Gao, Yishan Liu, Ziyi Wang, Haibin Wang, Chaofeng Han, Wenxiang Chu, Xuhua Lu.

  Neonatal mice achieve scar-free healing after spinal cord injury (SCI) by restoring microglial homeostasis, unlike adults, where persistent microglial dyshomeostasis drives scar expansion through mechanisms that remain elusive. Using RNA sequencing, we identified protein arginine methyltransferase 6 (PRMT6) as a key regulator of this disparity, upregulated in activated microglia at adult SCI lesions but maintained at low levels in neonatal microglia after injury. In adult mice, Prmt6 deficiency restored microglial homeostasis, evidenced by increased P2Y12/TMEM119 and reduced CD68, while reducing scar formation and enhancing axonal regrowth and motor recovery. Microglia-specific Prmt6 knockdown or PRMT6 inhibitor administration recapitulated these effects. Mechanistically, PRMT6 deposits H3R2me2a at the Ppargc1a promoter to repress peroxisome proliferator-activated receptor-γ coactivator-1α（PGC-1α）, thereby inhibiting fatty acid oxidation (FAO) and disrupting microglial homeostasis. Loss of Prmt6 alleviates this epigenetic repression, restoring FAO and microglial homeostasis. These findings establish PRMT6 as a novel epigenetic regulator linking microglial dyshomeostasis and metabolic dysfunction to maladaptive scar formation in adult SCI, highlighting PRMT6 inhibition as a promising therapeutic strategy to reprogram microglial metabolism and promote neural repair.

Keywords:  PGC‐1α; fatty acid oxidation; homeostasis; microglia; spinal cord injury

DOI:  https://doi.org/10.1002/advs.75325
Adv Sci (Weinh). 2026 Apr 14. e75125

Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.

Qianqian Li, Yajin Liao, Yan-Bo Zhao, Hongxing Wu, Tong Jin, Shuoshuo Li, Yuhan Liu, Peng Li, Songying Ouyang, Zekai Li, YuTing Xia, Qian Hua, Rui-Yuan Pan, Zengqiang Yuan.

  Dysregulated tricarboxylic acid (TCA) cycle activity is increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, yet the mechanistic underpinnings of the relationship remain unclear. Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5×FAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD-related pathological processes. Using structure-based screening and co-crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate-binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced β-amyloid (Aβ) deposition and significantly improved cognitive performance in 5×FAD mice. Collectively, our findings establish IDH1-mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.

Keywords:  IDH1; alzheimer's disease; kinsenoside; microglia; neuroinflammation; tca cycle

DOI:  https://doi.org/10.1002/advs.75125
Theranostics. 2026 ;16(10): 5105-5124

Host-directed nanotherapy for the treatment and imaging of tuberculous meningitis.

Elizabeth W Tucker, John Kim, Clara Erice, Anjali Sharma, Nerketa N L Damiba, Alvaro A Ordonez, Javier Allende Labastida, Nirnath Sah, Filipa Mota, Patricia de Jesus, Rhea Saini, Kelly F Schiaffino, Sanjay K Jain, Rangaramanujam M Kannan, Sujatha Kannan.

   Rationale: Tuberculous meningitis (TB meningitis) is a devastating infection where the host immune response drives brain injury. Standard adjunctive corticosteroids often fail to prevent neurological sequelae or improve survival in many populations. Host-directed therapies that can cross the blood-brain barrier (BBB) and reduce neuroinflammation are urgently needed. We evaluated a hydroxyl-terminated polyamidoamine (PAMAM) dendrimer as a theranostic nanoplatform to visualize and treat microglia-mediated neuroinflammation in a young rabbit model of TB meningitis.
Methods: A novel radiolabeled dendrimer (124I-dendrimer) was synthesized for noninvasive positron emission tomography (PET) imaging, with post-mortem gamma counting and fluorescent-labeled dendrimer (D-Cy5) confirming biodistribution. For therapy, rabbits with TB meningitis (i.e., infected) received weekly intravenous dendrimer-N-acetyl cysteine (D-NAC) or phosphate buffered saline (PBS). After two weeks, treatment efficacy was evaluated with longitudinal neurobehavioral scores and multimodal PET (18F-FDG for glucose metabolism, 18F-py-albumin for BBB integrity, and 124I-DPA-713 for microglial/macrophage activation). Post-mortem analyses included bacterial burden (colony-forming units [CFU]), cerebrospinal fluid (CSF) protein and cytokine levels, and brain immunohistochemistry for glial and white matter markers.
Results: 124I-Dendrimer demonstrated selective accumulation within brain lesions, co-localizing primarily with activated microglia. D-NAC significantly improved neurological outcomes and attenuated neuroinflammation and brain injury, even without antimicrobial therapy. Longitudinal PET imaging confirmed D-NAC efficacy, showing decreased neuroinflammation (124I-DPA-713) and improved BBB integrity (18F-py-albumin). Post-mortem analyses corroborated these findings, demonstrating that D-NAC reduced microglial inflammation and IL-17a levels, while improving myelination and BBB integrity.
Conclusions: This study establishes D-NAC as a promising host-directed theranostic strategy for TB meningitis and supports the clinical potential of dendrimer nanoplatforms to diagnose and treat central nervous system infections.

Keywords:  PET imaging; dendrimer; host-directed therapy; microglia; tuberculous meningitis

DOI:  https://doi.org/10.7150/thno.125729
J Adv Res. 2026 Apr 14. pii: S2090-1232(26)00341-3. [Epub ahead of print]

Platelet factors 4 produces an antidepressant effect in mice via inhibition of neuroinflammation.

Yi-Heng Li, Jin-Qiong Zhan, Ying Zhao, Zi-Ying Ouyang, Ling-Qing Luo, Bo Wei, Yuan-Jian Yang.

   INTRODUCTION: Platelet factor 4 (PF4) is secreted by platelets and can cross blood-brain barrier (BBB) to affect brain function, including regulations of neuroinflammation and synaptic plasticity, which are involved in the pathophysiology of depression. Nevertheless, whether PF4 participates in the development of depression has yet to be determined.
OBJECTIVES: The aim of this study was to investigate the role and the underlying mechanisms of PF4 in the pathophysiology of depression.
METHODS: Mouse models of depression were established using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) paradigms. Plasma levels of PF4 and inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). A battery of behavioral tests were conducted to evaluate the effects of systemic and intra-nucleus accumbens (NAc) administration of PF4 siRNA or PF4 on depressive-like behaviors. RNA sequencing (RNA-seq) for transcriptomic analysis and immunofluorescence staining were performed to assess neuroinflammatory status and microglial activation.
RESULTS: Plasma PF4 was significantly reduced in patients with major depression. Similarly, CSDS mice exhibited decreased PF4 levels in both plasma and the NAc. Systemic PF4 administration produced an antidepressant-like effect in naive mice and rescued depressive-like behaviors in both CSDS and LPS-treated mice. In CSDS mice, intravenous administration of PF4 suppressed peripheral inflammatory response and increased PF4 levels in the NAc. Knockdown of PF4 in the NAc induced depressive-like behaviors in mice and markedly elevated inflammatory levels in this region. Correspondingly, infusion of PF4 into the NAc mitigated neuroinflammation, inhibited microglial activation, and alleviated depressive-like behaviors in CSDS mice. RNA-seq analysis also confirmed the suppressive effect of PF4 on neuroinflammatory pathways in the NAc.
CONCLUSION: Our findings demonstrate that PF4 exert an antidepressant effect, at least in part, by suppressing neuroinflammatory responses within the NAc. This work identifies PF4 as a novel and promising therapeutic target for the treatment of major depression.

Keywords:  Depression; Microglia; Neuroinflammation; Nucleus accumbens (NAc); PF4

DOI:  https://doi.org/10.1016/j.jare.2026.04.037
Mol Ther. 2026 Apr 11. pii: S1525-0016(26)00277-7. [Epub ahead of print]

Promoting donor microglial replacement through augmented conditioning or radiation sensitivity.

Troy C Lund, Willa Durose, Emma Schindhelm, Megan M Constans, Erin E Nolan, Ashish O Gupta, Kai Braaten, Paul J Orchard.

Donor myeloid cells engraft the brain after hematopoietic cell transplant (HCT) which partially replace native microglia. The conditions which promote or maintain engraftment are not well known. Previously, we demonstrated mice that received a double HCT using radiation-based conditioning had higher brain engraftment, but also mortality of 70%. We now show that mice that undergo double HCT with busulfan preconditioning have nearly 70-80% brain engraftment and lower mortality of 8%. Using the radiation sensitive NSG mouse model, we found up to 15% donor myeloid (CX3CR1+) brain engraftment after low dose radiation (450 cGy) vs 0.1% in C57BL/6 mice treated similarly. NBSGW mice engraft the marrow without the need for conditioning, and we found the addition of radiation boosted brain engraftment greater than 10-fold from 0.3% (no conditioning) to 4.8% after HCT. A further increase in brain engraftment (median 22.5%) was observed when animals were pretreated with PLX3397, a microglia inhibitor which indicated that myeloid niche clearance promotes brain engraftment. In conclusion, preconditioning and niche clearance play an important role in brain engraftment. New ways of microglia replacement are needed if we are to avoid the use of preconditioning.

DOI: https://doi.org/10.1016/j.ymthe.2026.04.012
Mol Psychiatry. 2026 Apr 13.

Microglia respond to and induce anxiety and grooming in mice using calcium signaling.

Naveen Nagarajan, Mario R Capecchi.

Disruption of the mouse Hoxb8 gene causes chronic anxiety and pathological over-grooming resulting from defective Hoxb8 microglia. Furthermore, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety and/or grooming. Herein we show that the molecular signals for inducing anxiety and/or grooming in response to optogenetic activation are calcium ions. Conversely, induction of grooming and anxiety in mice produces calcium transients within microglia. Unexpectedly, calcium transients are not produced in Hoxb8 mutant mice in response to the induction of these behaviors. The likely cause for this lack of response by Hoxb8 mutant mice to induced grooming is the presence of high constitutive levels of free calcium within Hoxb8 mutant microglia resulting from the gene disruption. These calcium ions, in turn, serve as relentless signals to increase anxiety and grooming leading to chronic anxiety and pathological overgrooming in Hoxb8 mutant mice. Thus, we have shown that calcium signaling is used by microglia: 1) to induce anxiety and/or grooming by optogenetic stimulation of Hoxb8 microglia in WT mice, 2) to respond by microglia to the induction of both behaviors in WT mice and 3) as the causative agent for producing chronic anxiety and pathological overgrooming in Hoxb8 mutant mice.

DOI: https://doi.org/10.1038/s41380-026-03572-w
Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2521977123

Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.

Takafumi Kawai, Daisuke Yoshioka, Pattama Wiriyasermkul, Risa Mori-Kreiner, Rizki Tsari Andriani, Megumi Kobayashi, Manabu Abe, Kenji Sakimura, Kazuki Nagayasu, Shushi Nagamori, Yasushi Okamura.

  Voltage-gated proton channel Hv1/VSOP has long been regarded as a plasma membrane protein that modulates intracellular pH and membrane potential to support immune cell function. Here, we reveal an unexpected intracellular pool of Hv1 on endosomal membranes in microglia, where it orchestrates a reciprocal interplay between endosomal trafficking and the actin cytoskeleton. Combining endosome patch-clamp recordings with high-resolution imaging, we demonstrate that functional endosomal Hv1 forms tight and dynamic associations with F-actin. Genetic deletion of Hv1 markedly elongates actin filaments, a phenotype that appears to depend on intracellular rather than plasma membrane Hv1 activity. Heterologous expression of wild-type Hv1, but not a proton-non-conducting mutant, reduced the F-actin staining, indicating that the ion-conducting function is required for this regulation. Live-cell imaging reveals that Hv1-positive endosomes move in concert with F-actin networks and frequently engage with their terminal regions, suggesting that filament barbed ends are trapped at Hv1-positive endosomes. Proximity-labeling proteomics identifies the actin-capping protein CAPZ as a critical mediator of Hv1-dependent actin remodeling, and genetic ablation of CAPZ abolishes the actin phenotype in Hv1-deficient microglia. These findings uncover a previously unrecognized ion channel-cytoskeleton crosstalk that shapes endosomal function and microglial physiology, redefining the functional landscape of voltage-gated proton channels.

Keywords:  F-actin; endosome; microglia; voltage-gated proton channel

DOI:  https://doi.org/10.1073/pnas.2521977123
Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2523148123

Trem2 exacerbates ischemic brain injury through Gpnmb in a photothrombotic stroke model.

Xuezhen Chen, Kunyu Li, Siyu Liu, Junyi Zhao, Sagun Tiwari, Fan Zeng, Yue Zhao, Pingping Zhang, Han Tang, Hong Zhao, Helmut Kettenmann, Xianyuan Xiang, Xinzhou Zhu.

  Ischemic stroke is a major public health challenge, with microglia-mediated neuroinflammation exerting both protective and detrimental effects on neuronal survival. The Triggering receptor expressed on myeloid cells 2 (Trem2), predominantly expressed by microglia, has been reported to confer neuroprotection in the middle cerebral artery occlusion (MCAO) model. Paradoxically, in patients, elevated plasma soluble Trem2 (sTrem2) levels correlate with increased risk and poor outcomes. To test the impact of Trem2 function in the context of stroke, we utilized the photothrombotic stroke model which elicited strong Trem2 upregulation, a clinical feature which is not mimicked in MCAO models. Trem2 depletion reduced infarction volume, suppressed proinflammatory cytokine production, preserved neuronal survival, and lessened motor and neurological impairment. Conversely, intracerebral administration of sTrem2 exacerbated neuronal loss, amplified inflammation, and worsened neurological deficits. Integrated mouse-human transcriptomic analyses identified glycoprotein nonmetastatic B (Gpnmb) as a conserved downstream effector of Trem2. Soluble Gpnmb (sGpnmb) administration abolished the protective effects of Trem2 depletion, promoting microglial activation, lipid accumulation, and neuronal damage. Additionally, plasma sTrem2 and sGpnmb levels were elevated in stroke patients, positively correlated, and may serve as biomarkers of poor prognosis. These findings uncover a detrimental role for Trem2 in ischemic stroke, provide mechanistic insight into the link between sTrem2 and poor clinical outcomes, and identify the Trem2-Gpnmb axis as a potential therapeutic target to mitigate poststroke neuroinflammation.

Keywords:  Trem2; blood biomarker; ischemic stroke; middle cerebral artery occlusion model; photothrombotic model

DOI:  https://doi.org/10.1073/pnas.2523148123
J Neuroinflammation. 2026 Apr 14.

Neonatal sevoflurane exposure disrupts the lung-brain axis and drives microglial neuroinflammation and cognitive deficits.

Lirong Liang, Shuhui Cao, Youyi Zhao, Bing Liu, Jiachen Wang, Peiqin Gong, Yifei Wang, Guanghui Hao, Xingchen ZhangMu, Naining Lu, Haopeng Zhang, Shengxi Wu, Fang Kuang, Hui Zhang.

   BACKGROUND: Neonatal sevoflurane exposure in mice induces microglial activation and long-term cognitive deficits, a finding that raises significant concerns for pediatric anesthesia. The lung-brain axis, a critical pathway mediating pulmonary-central nervous system communication, is indispensable for maintaining organismal homeostasis. However, existing research on anesthetic neurotoxicity has focused predominantly on central mechanisms, with insufficient attention to the lung-a major immune organ with extensive bidirectional crosstalk with the brain. Herein, we aim to explore the lung-brain interactions underlying long-term cognitive sequelae of neonatal sevoflurane exposure.
METHODS: C57BL/6J mice were selected and exposed to 3% sevoflurane for 2 h daily on postnatal days 6-8. Upon reaching adulthood, cognitive function and microglial activation status were evaluated. At 4 weeks post-exposure, 16S rRNA gene sequencing and metabolomic analysis were performed respectively to characterize the structure of the pulmonary microbiota and the metabolite profile. Proximity ligation assay (PLA), fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), and co-immunoprecipitation (COIP) were employed to investigate the molecular mechanisms by which lung-derived metabolites mediate brain effects. Additionally, rescue experiments were conducted by administering the sphingosine-1-phosphate receptor modulator FTY720 and Moce to validate the aforementioned effects.
RESULTS: Repeated neonatal sevoflurane exposure impaired adult cognitive function, induced microglial activation, and was concurrent with pulmonary microbiome dysbiosis and metabolic alterations. Notably, sphingosine-a key membrane lipid-was significantly decreased. Intratracheal administration of FTY720, a sphingosine analog, alleviated neuroinflammation and ameliorated cognitive deficits. Mechanistically, sevoflurane exposure upregulated HDAC1 and downregulated KLF4, whereas FTY720 significantly rescued these sevoflurane-induced expression aberrations, implicating the HDAC1/KLF4 axis in the regulation of neuroinflammation. Additionally, MOCE significantly alleviated neuroinflammation and ameliorated cognitive deficits.
CONCLUSIONS: Developmental sevoflurane exposure induces microglial activation and cognitive decline via a pulmonary dysbiosis-sphingosine reduction cascade. The sphingosine-1-phosphate receptor modulator FTY720 mitigates this impairment by regulating microglial activation and neuroinflammation. These findings reveal novel mechanisms of anesthetic neurotoxicity and identify potential neuroprotective targets for pediatric anesthesia.

Keywords:  Development brain; Lung-brain axis; Microglia; Sevoflurane; Sphingosine

DOI:  https://doi.org/10.1186/s12974-026-03808-0
Research (Wash D C). 2026 ;9 1237

Type 2 Diabetes Promotes the Microglial Pyroptosis by Activating NLRP3 Inflammasome to Impede Remyelination After Spinal Cord Injury.

Jingyu Xu, Li Fang, Tao Wei, Shufang Cai, Ran Chen, Bingbin Wang, Saiqun Nie, Yueqi Wu, Fuyi Yan, Jiaqin Shao, Wenjun Wu, Ying Zhan, Ke Xu, Jian Xiao, Yanqing Wu.

Diabetes hinders nerve recovery after spinal cord injury (SCI). The complex pathological factors of diabetes increase the difficulty of treating diabetes combined with SCI. Maintaining normal microglial function is essential for SCI recovery. However, it is unclear whether diabetes hinders nerve recovery after SCI by influencing normal microglial function. This study explored the role and regulatory mechanism of diabetes in microglial function during SCI recovery. We constructed a type 2 diabetes (T2D) combined with SCI mouse model and confirmed that T2D hinders nerve repair after SCI. T2D blocked phagocytizing function of microglia in SCI mice, which results in increased myelin debris accumulation and poor remyelination. A mechanistic study demonstrated that T2D triggers activation of NLRP3 inflammasome by activating the RAGE-ROS-TXNIP axis and then induces excessive microglial pyroptosis, which consequently leads to considerable loss of microglia after SCI. Verapamil (VRP; a TXNIP inhibitor) treatment confirmed that TXNIP is necessary for NLRP3 inflammasome activation. Conditional microglial Caspase-1 gene knockout (KO) mice also confirmed that excessive microglial pyroptosis is an important inducing event for more severe nerve damage in T2D combined with SCI mice. Moreover, this T2D effect on increased microglial pyroptosis was also effectively reversed by N-acetyl-l-cysteine (NAC; an antioxidant) and N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1; a RAGE inhibitor). In conclusion, this study revealed that T2D induces increased microglial pyroptosis by activating the RAGE-ROS-NLRP3 axis, and then blocks remyelination after SCI, which strongly suggests that microglial pyroptosis may be the key target for treating T2D combined with SCI.

DOI: https://doi.org/10.34133/research.1237
Mater Today Bio. 2026 Jun;38 103055

An engineered ROS-responsive cascade nanoplatform delays Alzheimer's disease progression via Nrf2/GPX4-mediated microglial functional reprogramming.

Yang Yu, Jun-Jie Yu, Shuai-Wen Ding, Ge Zhang, Yang Liu, Rui-Bo Guo, Juan Zang, Xiang-Xuan Zhao, Xue-Tao Li, Liang Kong.

  Alzheimer's disease (AD) is driven by a self-amplifying pathological network in which microglia-mediated neuroinflammation, oxidative stress, and cerebral iron dyshomeostasis are tightly interconnected. Here, we report a ROS-responsive, cascade-targeted nanoplatform (KMAI@NPs) engineered to intervene at this microglia-centered regulatory hub. The nanoplatform integrates an acetylsalicylic acid-modified dextran self-assembly core with PEGylated peptide modules for cascade targeting. By systematically optimizing the dextran molecular weight and acetylsalicylic acid grafting ratio, the self-assembly behavior and in vivo stability of the nanoplatform were rationally tuned. KMAI@NPs efficiently penetrate the blood-brain barrier, exhibit prolonged circulation, and selectively target activated microglia. Mechanistically, KMAI@NPs regulate microglial polarization and inhibit ferroptosis. In particular, given that M2-polarized microglia are more susceptible to ferroptosis, KMAI@NPs further protect these beneficial cells from ferroptotic injury through activation of the Nrf2/GPX4 axis, thereby preserving their anti-inflammatory and neuroprotective functions under inflammatory and iron-overload conditions. In APP/PS1 transgenic mice, KMAI@NPs markedly alleviate neuroinflammation, iron overload, amyloid pathology, and neuronal ultrastructural damage, resulting in significant cognitive improvement. This work establishes a microglia-centered, multitarget nanotherapeutic strategy that enables coordinated regulation of neuroinflammation, oxidative stress, and iron dyshomeostasis in AD.

Keywords:  Alzheimer's disease; Ferroptosis; Microglial; Nrf2/GPX4

DOI:  https://doi.org/10.1016/j.mtbio.2026.103055
Cell Commun Signal. 2026 Apr 13.

Bindarit attenuates brain injury and neuroinflammation in status epilepticus by disrupting C3/C3aR signaling and modulating microglia-astrocyte interactions.

Jiancong Chen, Yanhong Hu, Jiaxin Xie, Haiping Zhou, Tingting Yang, Mingjia Yu, Jingwen Wu, Suyue Pan, Kaibin Huang.



Keywords:  Astrocyte; Bindarit; Complement C3; Microglia; Status epilepticus

DOI:  https://doi.org/10.1186/s12964-026-02876-2
J Med Virol. 2026 Apr;98(4): e70906

Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.

Lin Gao, Duo Cao, Wenhua Tao, Dongmei Zhang.

  Quercetin, a kind of flavonoids, has been implicated in multiple neurological diseases. Nevertheless, the functional roles and mechanisms of quercetin in HIV-associated neurocognitive disorders (HAND) remain unclear. HIV-1-encoded transactivator of transcription (Tat) is the major pathogenic factor for the progression of HAND. In the central nervous system, microglia-mediated Tat neurotoxicity is mainly comprised of inflammatory response, nitric oxide (NO) and excessive glutamate. In this study, we demonstrated that Tat-activated NF-κB p65 directly induce the release of IL-6 and TNF-α as well as NO production, while Tat promoted glutamate release via NF-κB/SPI1 pathway. Conversely, quercetin could upregulate SIRT3 expression to reduce reactive oxygen species (ROS) generation, thereby inhibiting NF-κB/SPI1 pathway and mitigating microglia-mediated Tat neurotoxicity. In addition, we also observed that quercetin alleviated neuronal apoptosis induced by the microglia-derived conditioned media in a SIRT3/ROS/NF-κB-dependent manner. Furthermore, Tat was found to downregulate SIRT3 expression via NF-κB/SPI1 pathway, which was reversed by quercetin in microglia. Thus, our data establish that quercetin disrupts the SIRT3/ROS/NF-κB/SPI1 feedback loop to attenuate microglia-mediated Tat neurotoxicity. Finally, in murine models, we recapitulated that administration of quercetin remarkably ameliorated Tat‑induced neuropathy and cognitive decline in vivo. Taken together, our study uncovers the neuroprotective roles of quercetin in the amelioration of microglia-mediated Tat neurotoxicity and highlights its potential as a therapeutic agent for the treatment of HAND.

Keywords:  HIV‐associated neurocognitive disorders; SIRT3; Tat; microglia; neurotoxicity; quercetin

DOI:  https://doi.org/10.1002/jmv.70906
Ecotoxicol Environ Saf. 2026 Apr 10. pii: S0147-6513(26)00449-5. [Epub ahead of print]316 120120

Activated microglia contribute to paraquat neurotoxicity through neuroinflammation and regulation of phenotypic polarization of astrocytes.

Huiming Yang, Yi Yang, Lili Yang, Zheng Li, Liang Lyu, Xiaofeng Zhang.

  Paraquat (PQ), a widely used bipyridyl herbicide, exerts neurotoxic effects on dopaminergic neurons and can lead to Parkinson's disease (PD)-like syndrome. Although immune dysfunction has been implicated in PD progression, the role of neuroimmune interactions in PQ-induced neurotoxicity remains poorly understood. This study aimed to investigate the mechanism by which microglia, the innate immune cells of the central nervous system, regulate the neurotoxic effects of PQ exposure. Network toxicology analysis revealed a link between microglia-mediated neuroinflammation and PQ-induced neurodegeneration, as well as astrocyte differentiation. Single-cell RNA sequencing (scRNA-seq) analysis identified the PI3K/AKT pathway as a potential regulatory mechanism underlying astrocyte phenotypic transformation. Our experimental evidence showed that PQ exposure induced neuroinflammation, dopaminergic neuron degeneration, and a pro-inflammatory astrocytes phenotype, all of which were reversed by microglial depletion. In vitro experiments using primary astrocytes cultured in conditioned medium from PQ-activated microglia demonstrated that activated microglia promoted a pro-inflammatory astrocyte phenotype, which was associated with inhibition of the PI3K/AKT pathway. This effect was alleviated by pretreatment with a PI3K activator. Taken together, our results suggest that PQ exposure disrupts microglia-astrocytes homeostasis, leading to aberrant neuroimmune crosstalk and inflammatory cascades that may underlie dopaminergic neurodegeneration. Therefore, this work provides crucial insights into the neuroimmune mechanisms of PQ-induced pathology, thereby informing both future research and environmental health policy.

Keywords:  Astrocytes; Microglia; Neuroinflammation; Neurotoxicity; Paraquat; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120120
Cell Death Discov. 2026 Apr 11.

TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.

Xiaoqian Wang, Hua Zhou, Yujie Zhai, Yunrong Zhang, Yao Cheng, Yi Yuan, Wenxiao Cao, Anqing Gao, Mengshuang Liu, Qiaoyun Wang, Hongliu Sun.

Febrile seizures (FS) are common convulsive episodes in childhood and an important etiological component in epilepsy. However, most currently available antiepileptic drugs cannot prevent epileptogenesis and may even exacerbate it. Triggering receptor expressed on myeloid cell 2 (TREM2)-mediated microglial phagocytosis of inhibitory synapses may play a pivotal role in epileptogenesis; however, the role of TREM2 in FS-induced epilepsy remains unclear. We established a Sprague-Dawley rat model of juvenile prolonged FS to analyze the associated molecular changes, epileptic susceptibility, and seizures. Our results confirmed that prolonged FS resulted in increased TREM2 levels, excessive phagocytosis by activated microglia targeting inhibitory synapses, and elevated epileptic susceptibility and seizures. Administration of a CD33 agonist (monosialoganglioside 1, GM1), a negative moderator of TREM2 that reduces its levels, attenuated microglial phagocytosis of inhibitory synapses and weakened susceptibility to epilepsy and seizures. The inhibitory effects of TREM2 knockdown were similar to those of CD33 activation. Blocking the outward-facing region of phosphatidylserine (PtdSer) to prevent TREM2 recognition resulted in increased TREM2 levels and deteriorated microglial activation. Finally, although vesicular GABA transporter (VGAT) levels were higher in the prolonged FS rats treated with annexin V, susceptibility to epilepsy and seizures were aggravated. This study revealed that reducing TREM2 levels may inhibit prolonged FS-induced epileptogenesis by alleviating the phagocytic function of activated microglia targeting inhibitory synapses, while preventing TREM2 from recognizing PtdSer has the opposite effect.

DOI: https://doi.org/10.1038/s41420-026-03118-7
Neuropsychopharmacology. 2026 Apr 16.

Functional genomic profiling of schizophrenia-associated genes reveals key microglial regulators.

Joy E Horng, Liam T McCrea, Rebecca E Batorsky, Joshua J Bowen, Camilla Boschian, Yoonjae Song, Roy H Perlis, Steven D Sheridan.

Microglia are increasingly recognized as key regulators of neural circuit development and putative contributors to the pathophysiology of neuropsychiatric disorders such as schizophrenia (SCZ). However, the functional impact of SCZ-associated genes in microglia remains largely unexplored. Here, we performed an arrayed CRISPR targeting screen of 30 SCZ-associated genes predicted to be differentially expressed in human microglia-like cells. Target genes were prioritized based on post-mortem transcriptomic relevance and predicted ontology-based roles in phagocytosis pathways. We quantified phagocytic activity and morphological changes following gene targeting using high-content confocal imaging. Key targets, including CYFIP1, MSR1, TREM2, SYK, ITGB2, ITGAM, and IRF8, modulated phagocytosis and altered morphological properties consistent with activation states, validating their functional roles in microglia. To elucidate transcriptional impact, we further applied a multiplexed RNA sequencing platform across gene targets. These analyses revealed gene-specific transcriptional signatures, implicating divergent pathways related to phagocytic, activation, cytoskeletal, and lysosomal function. Together, these findings demonstrate the utility of CRISPR-based functional genomics in characterizing microglia function and identifying new target genes and mechanisms that may underlie their contributions to SCZ pathophysiology.

DOI: https://doi.org/10.1038/s41386-026-02406-1
Neural Regen Res. 2026 Apr 14.

Therapeutic potential of concentrated growth factor for spinal cord injury: Targeting microglial polarization and inflammation regulation.

Ziming Wang, Yubao Lu, Ju Fang, Zhizhong Shang, Wei Zhang, Jiale He, Mianshui Wan, Limin Rong.

  Excessive neuroinflammation following spinal cord injury is a key obstacle that hinders neurological functional recovery. Concentrated growth factor greatly enhances structural repair and functional recovery in damaged spinal cord, providing sustained and spatially specific anti-inflammatory regulation during the acute, subacute, and chronic stages of spinal cord injury. Therefore, this study aimed to evaluate the therapeutic potential of concentrated growth factor in a mouse model of traumatic spinal cord injury and its underlying mechanism. Our results showed that local injection of concentrated growth factor immediately after injury facilitated neurological functional recovery, indicated by improved gait parameters, increased motor evoked potential amplitude, reduced cystic cavities formation, enhanced neuronal survival, strengthened synaptic connections between serotonergic axons and resident neurons, and inhibited collagen deposition forming fibrotic scars. Concentrated growth factor demonstrated spatiotemporally specific anti-inflammatory effects, modulating the immune response by decreasing mediators of inflammation and enhancing anti-inflammatory signaling. The findings indicated that the core mechanism involved regulating microglial polarization states. In both the in vivo spinal cord injury model and an in vitro lipopolysaccharide-stimulated cell model, concentrated growth factor stimulated the polarization of microglial cells away from the inflammation-associated M1 type toward the restorative M2 type. The results further showed that concentrated growth factor inhibited the Toll-like receptor 4/nuclear factor κB and phosphatidylinositol 3-kinase/protein kinase B signaling pathways, suppressing NOD-like receptor family pyrin domain containing 3 inflammasome activation, which may drive the microglial polarization shift and alleviate neuroinflammation. This study focused on the core challenge of secondary neuroinflammation after spinal cord injury, and suggests that concentrated growth factor has potential as a multitarget biological treatment approach. By identifying the key role of microglial polarization in regulation and the core molecular mechanism of simultaneously inhibiting the Toll-like receptor 4/nuclear factor κB and phosphatidylinositol 3-kinase/protein kinase B signaling pathways, our work highlights concentrated growth factor as a potential strategy to achieve neuroprotection, inflammatory regulation and functional reconstruction in spinal cord injury.

Keywords:  NOD-like receptor family pyrin domain containing 3 inflammasome; Toll-like receptor 4/nuclear factor kappa B pathway; autologous biomaterial; concentrated growth factor; functional recovery; inflammatory regulation; microglial polarization; neuroprotection; phosphatidylinositol 3-kinase/protein kinase B pathway; spinal cord injury

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01105