bims-microg 2026-05-10 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–05–10
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia-dependent regulation of fear memory extinction.
Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.
Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
Neuroinflammation and neurodegeneration trigger a specific splice form of ribosomal protein S24.
Abi3S212F Alzheimer's disease variant alters plaque structure and disrupts microglia.
USP4 modulates ZBP1 ubiquitination to regulate microglial PANoptosis and functional outcomes following traumatic brain injury.
A Monocyte-Targeted Nanoplatform for Phagocytosis Activation and Ferroptosis Inhibition in Intracerebral Hemorrhage.
Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.
An unrecognized mechanism of neuroprotection by microglial TIA1-mediated stress granules to prevent neuroinflammation and demyelination in experimental autoimmune encephalomyelitis mice through sequestering ApoE mRNA.
LAPF enhances lysosomal acidification to promote TLR9 and cGAS-STING-mediated antiviral immunity and attenuate HSV-1-induced neuroinflammatory pain.
Loss of astrocytic Bmal1 promotes blood-brain barrier disruption and synaptic dysfunction during systemic inflammation.
Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.
TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress.
Iba1 deficiency impairs microglial synaptic remodeling and neuronal survival after axonal injury.
C1q-mediated synapse loss by microglial phagocytosis is associated with postoperative neurocognitive disorder in mice.
Rescuing prefrontal cortical excitation-inhibition imbalance with early-life microglial ablation ameliorates ASD-like behaviors in male BTBR mice.
Gas6 restores microglial efferocytosis and limits neuroinflammation in neonatal hypoxic-ischemic encephalopathy by activating MerTK and the PI3K-Rac1 pathway.
TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.
Peripheral nerve injury increases the probability of thalamocortical burst firing remotely via microglia-dependent enhancement of tonic inhibition.
Ferroptosis-associated myeloid cell heterogeneity and inflammatory amplification following spinal cord injury.

Nat Neurosci. 2026 May 04.

Microglia-dependent regulation of fear memory extinction.

Yunlong Liu, Jiaoyang Wo, Emily E Kramer, Xiaoyu Chen, Sungmo Park, Shuo Huang, Catherine Lin, Sheena A Josselyn, Paul W Frankland.

Traumatic events produce enduring memories that may be attenuated through extinction learning. Previous work has identified neuronal mechanisms underlying extinction learning that involve the remodeling or inhibition of neuronal ensembles (or engrams) that support the original fear memory. Here we identify a role for microglia in extinction learning in mice. We show that, during extinction, microglia are recruited to the soma and dendritic processes of fear engram neurons in the dentate gyrus. Interactions between microglia and somata mediate transient silencing of engram neurons. Inhibition of microglial recruitment to somata attenuated extinction-induced reductions in engram reactivity and slowed extinction. By contrast, interactions between microglia and dendritic processes promote engulfment of engram synapses and remodeling of engram neurons. Blocking complement signaling in engram neurons prevented extinction-induced engram neuron remodeling and slowed extinction. Together, these findings identify microglia as key regulators of fear engram expression and remodeling during extinction learning.

DOI: https://doi.org/10.1038/s41593-026-02286-0
Sci Immunol. 2026 May 08. 11(119): eadw5197

Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.

Juan Villar-Vesga, Donatella De Feo, Pauline Clément, Viola Bugada, Elèni Meuffels, Hannah Van Hove, Mitchell Bijnen, James King, Sophie Grundschober, Can Ulutekin, Maria Pena-Francesch, Sara Costa-Pereira, Laura Oberbichler, Violetta Gogoleva, Jeanne Kim, Katarina Wendy Schmidt, Musadiq A Bhat, Deborah Greis, Frauke Seehusen, Francesco Prisco, Urvashi Dalvi, Dietmar Benke, Bettina Schreiner, Tommaso Patriachi, Florian Ingelfinger, Isabelle C Arnold, Christian Münz, Melanie Greter, Aiman S Saab, Burkhard Becher, Sarah Mundt.

Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely believed to drive tissue damage in multiple sclerosis (MS), yet the distinct roles of central nervous system (CNS)-resident versus CNS-invading MPs remain unclear. Here, we combined single-cell profiling and conditional gene targeting to map and modulate ROS production across CNS MPs in a preclinical mouse model of MS. We show that monocyte-derived macrophages (MdMs) exhibit a higher oxidative stress gene signature and produce more ROS than microglia (Mglia). Challenging previous assumptions, our findings reveal that phagocytic NADPH oxidase 2 is dispensable for neuroinflammation. In contrast, quenching mitochondrial ROS (mtROS) through mitochondria-targeted catalase (mCAT) expression in MdMs, but not in Mglia, ameliorated disease severity in acute neuroinflammation. Although core phagocyte functions were unaltered in mCAT-expressing MdMs, our results demonstrate a direct neurotoxic role of mtROS. In sum, we identify MdMs as the primary driver of ROS-mediated oxidative neurological tissue damage.

DOI: https://doi.org/10.1126/sciimmunol.adw5197
Nat Commun. 2026 May 07.

Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.

Xiao-Wen Zhang, Xiao-Ming Ye, Ran Wang, Yong-Dong Guo, Ling Li, Yang Chen, Ting-Ting Liu, Xiao-Qing Zhou, Yu-Qi Wang, Zhong-Yao Li, Zhi-Yuan Lu, Zhi-Yong Du, Wei Zhou, Bo Han, Peng-Fei Tu, Qi-Xin Chen, Chun-Hong Zheng, Ke-Wu Zeng.

Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.

DOI: https://doi.org/10.1038/s41467-026-72779-w
Brain. 2026 May 06. pii: awag166. [Epub ahead of print]

Neuroinflammation and neurodegeneration trigger a specific splice form of ribosomal protein S24.

Srivathsa S Magadi, Maria Jonson, Pablo B Lucena, Michele F Caliandro, Beatriz Almeida, Lorina Bilalli, Dimitri Budinger, Anna Tsoi, Maria Ntzouni, Joseph Agi Maqdissi, Lech Kaczmarczyk, Jente J Zijlstra, Matej Faketija, Matthew Perkins, Gesine Paul, Martin Hallbeck, Martin Ingelsson, Joel C Watts, Nicole Reichenbach, Gabor C Petzold, Rico Schieweck, Michael T Heneka, Walker S Jackson.

  Neuroinflammation, particularly that involving reactive microglia, the brain's resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases (NDs). Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein-synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggests functional ribosome specialization through variation in their protein composition. Among RPs, S24, encoded by RPS24 in humans and Rps24 in mice, is unique as its transcripts undergo alternative splicing to produce protein variants with different C-terminal sequences that are differentially expressed across tissues and cell types. Understanding heterogeneous RP expression patterns across brain regions and cell types could reveal mechanisms underlying selective vulnerability in NDs and provide new biomarkers for neuroinflammatory responses. To identify RP expression patterns across brain regions in neurons, astrocytes, and microglia we analyzed cell type-specific translating mRNAs from mice. To investigate Rps24 isoform-specific expression, we performed cell type-resolved transcript analysis and developed antibodies specific for the S24-PKE protein variant encoded by mRNA isoform Rps24c. We examined Rps24c/S24-PKE expression in brains from mouse models of aging and neurodegeneration, as well as in human postmortem tissue from patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This work revealed distinct RP expression patterns across brain regions and between neurons, astrocytes, and microglia, including neuron-enriched RPs Rpl13a and Rps10. Analysis of RP paralogs revealed complex expression relationships with their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Across brain regions and cell types, Rplp0 and Rpl13a, commonly used normalization references, showed heterogeneous expression, raising important methodological considerations for gene expression studies. Rps24 isoforms exhibited striking cell type-specific expression patterns. Rps24c was predominantly expressed in microglia and was increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. Using S24-PKE-specific antibodies, we verified increased expression of this protein variant in brains with AD, PD, and HD, and in relevant mouse models. These findings establish heterogeneous RP expression as a feature of brain cell types which may enable cell type-specific translation regulation via specialized ribosomes. This work also identifies Rps24c/S24-PKE as a potential novel marker for neuroinflammation and neurodegeneration and provides new tools for monitoring these responses.

Keywords:  Neurodegeneration; Neuroinflammation; RNAseq; RiboTag; Ribosomal proteins; translatome

DOI:  https://doi.org/10.1093/brain/awag166
Alzheimers Dement. 2026 May;22(5): e71452

Abi3S212F Alzheimer's disease variant alters plaque structure and disrupts microglia.

Claire A Butler, Min Sung Gee, Katie O'Gara, Giedre Milinkeviciute, Celia Da Cunha, Shimako Kawauchi, Yueh-Hao Lu, Nellie Kwang, Kate I Tsourmas, Christiana Prekopa, Zechuan Shi, Heidi Yahan Liang, Sherilyn D Collins, Zachary A Pashkutz, Jenna A Sanchez, Kai-Xuan Shi, Amber D Walker, Shuling Wang, Maigan L A Wong, Karina Genaro, Jonathan Neumann, Angela Gomez-Arboledas, Duc M Duong, Nicholas T Seyfried, Andrea J Tenner, Frank M LaFerla, Ali Mortazavi, Vivek Swarup, Grant R MacGregor, Kim N Green.

   BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3S209F (Abi3S212F in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown.
METHODS: An Abi3S212F mouse was developed and crossed with two humanized amyloid beta (Aβ) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single-cell analyses across the lifespan.
RESULTS: Abi3S212F produced a dysfunctional microglial state that reduced dense-core plaque compaction, selectively lowering dense-core burden without affecting diffuse or total Aβ. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human Aβ but occurring even without plaques, indicating plaque-independent vulnerability. Spatial transcriptomics revealed an age-dependent shift toward an Abi3-high state that predisposes microglia to degeneration.
DISCUSSION: Abi3S212F produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.

Keywords:  ABI3; Alzheimer's disease; Aβ; cell death; microglia

DOI:  https://doi.org/10.1002/alz.71452
Cell Death Differ. 2026 May 06.

USP4 modulates ZBP1 ubiquitination to regulate microglial PANoptosis and functional outcomes following traumatic brain injury.

Feng Shuang, Nan Li, Tianwei Guo, Danfeng Zhang, Hang Zhu, Xin Jin, XiaoLin Qu, Ruting Wei, Hui Luo, Chao Lin.

Secondary damage in traumatic brain injury (TBI) is characterized by the abnormal release of damage-associated molecular patterns and excessive production of pro-inflammatory cytokines. Neuroinflammation is a hallmark of TBI. However, the mechanisms through which immune cells contribute to cognitive deficits and secondary inflammatory pathology remain poorly understood. In this study, we found that ZBP1-mediated microglial PANoptosis, which is a distinct form of innate immune-driven inflammatory cell death, is triggered following TBI. We further determined that microglial PANoptosis is induced by the synergistic action of heme and TNF-α. Mechanistically, we identified USP4 as a critical deubiquitinase for ZBP1 in microglia. USP4 was found to interact with, deubiquitinate, and stabilize ZBP1. Notably, AKT-mediated phosphorylation was found to be essential for maintaining USP4 protein stability. Pharmacological inhibition of USP4 using Vialinin A led to ZBP1 degradation, reduced microglial PANoptosis, and the amelioration of TBI-related functional deficits. Moreover, USP4 expression levels were found to be negatively correlated with prognosis patients with severe TBI. Collectively, our findings highlight a crucial role for USP4 in facilitating ZBP1-mediated inflammasome activation, microglial death, and cognitive impairment post-TBI, underscoring its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41418-026-01749-y
Small. 2026 May 08. e14883

A Monocyte-Targeted Nanoplatform for Phagocytosis Activation and Ferroptosis Inhibition in Intracerebral Hemorrhage.

Qingnian Li, Jing Wang, Jie Miao, Dexian Liu, Wanying Xiong, Bo Xiao, Wenhu Zhou.

  Intracerebral hemorrhage (ICH) is a highly fatal subtype of stroke characterized by vascular rupture and hematoma formation, leading to both primary mechanical damage and secondary neuroinflammatory injury. While both microglia and infiltrating monocytes contribute to hematoma clearance, their distinct roles and therapeutic potential remain unclear. Moreover, the erythrophagocytic process is tightly constrained by the CD47-SIRPα signaling axis, which impairs effective resolution. Through integrated multi-omics analysis, single-cell RNA sequencing, and cross-species validation, we identified that monocyte-derived macrophages (MDMs)-not resident microglia-are the predominant phagocytes in the ICH microenvironment, exhibiting superior hematoma clearance capacity. However, excessive red blood cell engulfment induces ferroptosis in these cells, thereby disrupting tissue repair. To address these challenges, we engineered a multifunctional nanoparticle system, mPDA@DFO-CpG-N1, incorporating: (1) a high-affinity monocyte-targeting aptamer (N1) for selective delivery; (2) a TLR9 agonist (CpG) that bypasses CD47-mediated inhibition by reprogramming monocytes energy metabolism to enhance phagocytic function; and (3) the iron chelator deferoxamine (DFO) to mitigate ferroptosis. The system utilizes endogenous monocyte chemotaxis for hematoma targeting and pH-sensitive release for spatiotemporal precision. In vivo studies in a murine ICH model demonstrated that mPDA@DFO-CpG-N1 achieved a 3.2-fold increase in lesion site accumulation, markedly improved hematoma clearance, suppressed monocytes ferroptosis, and significantly restored neurological function. This work reveals the pivotal role of MDMs in ICH resolution and presents a closed-loop, multimodal therapeutic strategy integrating targeted delivery, immune modulation, and cell fate regulation for effective treatment of cerebral hemorrhage.

Keywords:  TLR9 agonist; aptamer; intracerebral hemorrhage; iron chelation; monocyte‐derived macrophages; nanoparticle drug delivery

DOI:  https://doi.org/10.1002/smll.202514883
J Neuroinflammation. 2026 May 04.

Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.

Verónica López-López, Gerard Iniesta, Marcos Galán-Ganga, Alejandro Expósito-Coca, Violeta Durán-Laforet, Aysha M Bhojwani-Cabrera, Carmen M Navarrón, Marina Guillot-Fernández, Jose L Venero, Jose V Sánchez-Mut, Angel Barco, Albert Giralt, José P López-Atalaya.

  Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.

Keywords:  Alzheimer’s disease; Interferon; Microglia; Neuroinflammation; Sex differences; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12974-026-03840-0
J Neuroinflammation. 2026 May 04.

An unrecognized mechanism of neuroprotection by microglial TIA1-mediated stress granules to prevent neuroinflammation and demyelination in experimental autoimmune encephalomyelitis mice through sequestering ApoE mRNA.

Qinjiao Fu, Yanzhu Liu, Fangfang Li, Yanjiao Wang, Juanqing Yue, Yingyi Chen, Shufang Wu, Jingjing Zhang, Mengxian Jia, Yaozhi He, Jiawei Wang, Zhihui Huang, Ying Wang.

  Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular stress to microglia-mediated immune responses in MS remain elusive. Stress granules (SGs) serve as an adaptive response of cells to various stressors such as viral infection and oxidative stress. In this study, we found that microglial T-cell intracellular antigen 1 (TIA1), a core SG component, was upregulated in MS patients and experimental autoimmune encephalomyelitis (EAE) mice. The neuroinflammation, demyelination and clinical deficits were exacerbated in Tia1Cx3cr1-CKO (TIA1 knockout in microglia and monocyte-derived macrophages) EAE mice. Furthermore, TIA1-/- microglia exhibited the heightened activation characterized by increased proliferation, enhanced phagocytic activity, and a sustained polarization toward a pro-inflammatory phenotype. Notably, in an in vitro model of NaAsO2-induced stress, TIA1 deficiency in BV2 cells and primary cultured microglia resulted in both enhanced phagocytic capacity and a pro-inflammatory phenotypic shift. Mechanistically, upon to stresses, microglial TIA1-mediated SGs formation was enhanced, leading to sequester ApoE mRNA into SGs to reduce ApoE expression, which in turn prevented excessive activation of microglia and inhibited demyelination in EAE mice. These findings uncover a previously unrecognized neuroprotective mechanism wherein TIA1-mediated SGs in microglia dynamically restrain neuroinflammation via post-transcriptional control of ApoE, revealing a new therapeutic avenue for MS.

Keywords:  ApoE; Demyelination; Multiple sclerosis; Neuroinflammation; Stress granules; T-cell intracellular antigen 1

DOI:  https://doi.org/10.1186/s12974-026-03833-z
J Neuroinflammation. 2026 May 08.

LAPF enhances lysosomal acidification to promote TLR9 and cGAS-STING-mediated antiviral immunity and attenuate HSV-1-induced neuroinflammatory pain.

Erliang Kong, Mengqiu Deng, Ruifeng Ding, Mei Yang, Yongchang Li, Xudong Feng, Honghao Song, Huawei Wei, Xin Jiang, Hongbin Yuan, Chaofeng Han.

  Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like neuropathic pain and has been widely used as a model for studying virus-induced neuroinflammatory pain. However, the immune mechanisms underlying virus-induced neuroinflammation and pain remain incompletely understood. In this study, we used an HSV-1-induced neuroinflammatory pain model and observed reduced Lapf expression following HSV-1 infection through transcriptome sequencing, which was further confirmed to be localized in microglia of the spinal dorsal horn by immunofluorescence staining. Lapf microglia-specific deficiency aggravated neuroinflammation and promoted mechanical allodynia by impairing antiviral innate immunity both in vivo and in vitro. Overexpression of Lapf in microglia strengthened antiviral innate immunity and suppressed HSV-1 replication. Mechanistically, transcriptome sequencing of Lapf microglia-specific deficient mice identified lysosomal endocytosis as a critical pathway in LAPF-mediated antiviral innate immunity. Lapf deficiency decreased lysosomal acidity, resulting in reduced TLR9 activation, thereby impairing viral DNA sensing and IFN-I production. Lapf deficiency also reduced lysosomal membrane stability, facilitating the escape of HSV-1 DNA into the cytoplasm, where it could amplify and reactivate. Conversely, Lapf overexpression enhanced lysosomal acidity and membrane stability, promoting TLR9 activation and antiviral innate immunity. Furthermore, Lapf deficiency markedly reduced the phosphorylation of STING, TBK1, and IRF3, whereas Lapf overexpression restored cGAS-STING signaling. This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain.

Keywords:  Antiviral innate immunity; LAPF; Lysosomal acidification; Lysosomal membrane stability; Neuroinflammation; Postherpetic neuralgia

DOI:  https://doi.org/10.1186/s12974-026-03856-6
J Neuroinflammation. 2026 May 06.

Loss of astrocytic Bmal1 promotes blood-brain barrier disruption and synaptic dysfunction during systemic inflammation.

Changjun Lee, Yelin Lee, Woo Chan Jeong, Inhwa Hwang, Harin Bae, Do-Wan Shim, Hyeji Jung, Ji Won Um, Je-Wook Yu.

  Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, we identify the astrocytic circadian clock as a key regulator of BBB homeostasis during systemic inflammation. In a mouse model, circadian rhythm disruption for three weeks markedly increased BBB permeability in male mice, as evidenced by Evans blue leakage and myeloid cell infiltration into the brain parenchyma following lipopolysaccharide (LPS) challenge. Transcriptomic analyses using public datasets revealed that astrocytes exhibit the highest expression of core circadian clock genes among brain cell types. Accordingly, we generated tamoxifen-inducible, astrocyte-specific Bmal1-knockout (KO) mice. Deletion of Bmal1 in astrocytes significantly enhanced BBB leakage, astrogliosis and pericyte loss after LPS administration. Mechanistically, Bmal1-deficient astrocytes produced elevated levels of the chemokine CXCL5, which promoted CXCR2-dependent neutrophil recruitment into the brain. Pharmacological blockade of CXCR2 with SB225002 restored pericyte coverage and attenuated BBB disruption in astrocytic Bmal1 KO mice. Functionally, these mice exhibited impaired excitatory synaptic transmission following systemic inflammation, suggesting that astrocytic Bmal1 loss compromises neurovascular and synaptic integrity. Taken together, our findings demonstrate that astrocytic Bmal1 maintains BBB integrity and synaptic stability under inflammatory stress. This work also highlights astrocyte-intrinsic circadian regulation as a critical mechanism linking chemokine production to neurovascular vulnerability.

Keywords:  Blood-brain barrier; Bmal1; CXCL5; astrocyte; circadian rhythm

DOI:  https://doi.org/10.1186/s12974-026-03841-z
J Neuroinflammation. 2026 May 02.

Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.

Yuwen Wen, Ya-Nan Dou, Xiaohong Chen, Xiuxing Liu, Zhenlan Yang, Yingting Zhu, Zhidong Li, Caibin Deng, Ye Deng, Wenru Su, Yehong Zhuo.

  Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2fl/flCx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.

Keywords:  Acarbose; Acetylation; Immunometabolism; Microglia; Pkm2; Retinal ischemia and reperfusion

DOI:  https://doi.org/10.1186/s12974-026-03838-8
J Neuroinflammation. 2026 May 08.

TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress.

Nikolai Malorny, Bruno Chausse, Babak Khodaie, Amr Elgez, Lennart Söder, Andrea Lewen, Alexei V Egorov, Oliver Kann.

   BACKGROUND: The cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microglial cells (resident central nervous system macrophages), including the impact on neuronal survival, excitability, and synaptic transmission is incompletely defined, however. We explored the effects of chronic TNF-α exposure (72 h) on microglia and neurons in organotypic hippocampal slice cultures from male and female rats, i.e., postnatal cortex tissue lacking leukocyte invasion and adaptive immunity.
METHODS: We applied gene expression analysis, biochemical assays, immunohistochemistry, electrophysiology by extracellular (local field potential) and intracellular (intrinsic membrane properties) recordings, and pharmacological ablation of the microglial cell population. We mainly focused on carbachol-induced neural network oscillations (brain waves) in the gamma frequency band (30-70 Hz) that underlie higher cognitive functions such as perception, attention, and memory.
RESULTS: TNF-α induced microglial proliferation and upregulation of genes related to inflammation and oxidative stress such as Il6 (interleukin-6), Nos2 [inducible nitric oxide (NO) synthase, iNOS] and Sod2 (superoxide dismutase 2), which was accompanied by a decreased number of slices showing gamma oscillations in extracellular recordings. Notably, a fraction of slices presented neural bursting reflecting hyperexcitability in the tissue. Neuronal dysfunction was absent during acute TNF-α exposure (30 min). When paired with the lymphocyte cytokine interferon-gamma (IFN-γ), TNF-α induced an amplified neuroinflammation response dominated by bursting or loss of electrical activity. In intracellular recordings, neurons showed a brief burst of action potentials followed by slowing of spiking with pronounced afterhyperpolarization (switch from regular to burst firing behavior) during depolarizing current injection. Notably, the impairments could be attenuated by inhibition of iNOS and NADPH oxidase, glucose supplementation, microglial depletion or blockade of TNF receptor 1 (TNFR1) signaling with small molecule drugs, RIPA-56 and ICCB-19.
CONCLUSIONS: Our data provide mechanistic insight into TNF-α- and IFN-γ-induced neuronal impairments mediated by microglial NO, metabolic and oxidative stress, and demonstrate functional neuroprotection by pharmacology. Our study extends the pathophysiological understanding of diseases such as sepsis, multiple sclerosis, Alzheimer's disease, depression and schizophrenia featuring activated microglia, infiltrating monocytes and T cells, and/or blood-brain barrier leakage.

Keywords:  Action potential; Cytokines; Electrophysiology; Energy metabolism; Gamma oscillations; Microglial cells; Neuroinflammation; Neuronal cell death; Reactive oxygen and nitrogen species (ROS/RNS)

DOI:  https://doi.org/10.1186/s12974-026-03835-x
J Neuroinflammation. 2026 May 07.

Iba1 deficiency impairs microglial synaptic remodeling and neuronal survival after axonal injury.

Koji Sekiguchi, Hirotaka Shoji, Tomoko Shindo, Jumpei Sasabe, Daiki Tokuyasu, Jin Nakahara, Tsuyoshi Miyakawa, Daisuke Ito.

   BACKGROUND: Microglia remodel neuronal circuits in pathological conditions; however, the molecular requirements for these responses and their consequences for motoneuron survival remain unclear.
METHODS: Aif1 (Iba1) knockout mice were generated using CRISPR/Cas9-mediated deletion, and baseline phenotypes and responses to unilateral facial nerve axotomy were assessed using immunohistochemistry, transmission electron microscopy, and single-nucleus RNA sequencing of the facial motor nucleus. Motoneuron survival and nuclear γH2AX foci were evaluated 28 days post-axotomy.
FINDINGS: Under baseline conditions, Iba1-/- mice had reduced body weights and mild behavioral abnormalities compared to wild-type mice. After axotomy, microglial ensheathment of ChAT-positive facial motoneurons was reduced, with fewer neurons showing extensive perisomatic microglial coverage than in Iba1+/+ mice. Ultrastructurally, somatic synapse loss observed after injury in wild-type mice was not detected in Iba1-/- mice, and fewer injured motoneurons were in contact with microglial processes. Single-nucleus transcriptomics showed an exaggerated expansion of an interferon-responsive microglial state in Iba1-/- mice after axotomy, whereas injured motoneurons displayed altered transcriptional programs related to synapse organization and neurotransmission. At 28 days, Iba1-/- mice showed reduced motoneuron survival, lower ChAT expression, and increased nuclear γH2AX foci.
INTERPRETATION: Iba1 supports microglia-neuron cross-talk that enables effective perisomatic remodefling after axonal injury; disruption of this response is accompanied by inflammatory-state shifts and compromised motoneuron survival.

Keywords:  Facial nerve axotomy; Integrated analysis; Microglia; Microglia–neuron interaction; Neuronal survival; Synaptic remodeling; Synaptic stripping

DOI:  https://doi.org/10.1186/s12974-026-03848-6
Br J Anaesth. 2026 May 06. pii: S0007-0912(26)00133-9. [Epub ahead of print]

C1q-mediated synapse loss by microglial phagocytosis is associated with postoperative neurocognitive disorder in mice.

Jingjing Lv, Liang Yao, Lili Tang, Qibing Li, Lixia Wang, Xunchuan Yan, Mengmeng Li, Wenjing Peng, Huiwen Zhang, Jiaxin Guo, Juntao Weng, Bin Mei, Jiqian Zhang, Zhilai Yang, Qiying Shen, Yao Lu, Yongquan Chen, Jun Hu, Mervyn Maze, Xuesheng Liu.

   BACKGROUND: Perioperative neurocognitive disorders (PNDs) are common complications in elderly surgical patients. Possible pathogenic mechanisms for the development of PNDs include loss of synaptic connections mediated by microglial activation, although the precise mechanisms are not fully understood.
METHODS: Male and female C57BL/6J or male Cx3cr1-CreERT2 mice, aged 8-12 weeks, were subjected to aseptic tibial fracture surgery, and cognitive tests were carried out 3 days after surgery. Through a combination of bulk RNA sequencing, Western immunoblotting, immunofluorescence, and Golgi staining of the hippocampus, we investigated the role of complement C1q in activating microglia and phagocytosing synaptic connections in the pathogenesis of postoperative neurocognitive disorder.
RESULTS: Postoperative mice displayed memory deficits in both the Y-maze (P<0.001) and the trace fear conditioning (TFC) paradigms (P=0.002); these memory deficits were associated with increased microglial activation, complement C1q upregulation, classical complement pathway transcriptomic upregulation, and synapse loss (all P<0.05). After surgery, there was a ∼2-fold increase in colocalisation of C1qa with Homer1 (excitatory) or gephyrin (inhibitory) synaptic proteins in microglia (P<0.001). Postoperative memory decline and synapse loss did not occur after treatment with microglial activity inhibitor minocycline, after exposure to C1q neutralising antibody JL-1, or after C1q depletion from CA1 microglia. Activation of NF-κB was correlated with elevated levels of complement C1q in models, and selective inhibition of NF-κB activation with pyrrolidinedithiocarbamate ammonium (PDTC) attenuated the surgery-induced elevation of C1q and improved cognitive function.
CONCLUSIONS: The results demonstrate that hippocampal microglia prune both excitatory and inhibitory synapses in a C1q-dependent manner, contributing to postoperative synapse loss and cognitive dysfunction. Targeting C1q and NF-κB activation could be a promising therapeutic intervention to ameliorate perioperative neurocognitive disorders.

Keywords:  complement C1q; hippocampus; microglia; perioperative neurocognitive disorders; synaptic pruning

DOI:  https://doi.org/10.1016/j.bja.2026.02.024
Brain Behav Immun. 2026 May 01. pii: S0889-1591(26)00542-8. [Epub ahead of print]136 106794

Rescuing prefrontal cortical excitation-inhibition imbalance with early-life microglial ablation ameliorates ASD-like behaviors in male BTBR mice.

Xinggao Zhang, Meifeng Gong, Zhenyang Chen, Jing Luo, Zijun Zhao, Zhirui Wu, Jinghui Zhao, Yuanyuan Ma, Lina Nie, Xiaotang Fan.

  Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside the presence of restricted and repetitive behaviors. Microglia, the resident immune cells of the central nervous system, play a crucial role in the development of ASD by regulating synaptic development and plasticity. In this study, we investigate the pharmacological effects and underlying cellular mechanisms of PLX3397 (PLX), a selective inhibitor of the colony-stimulating factor 1 receptor (CSF1R), for the pharmacological ablation of microglia in the context of ASD treatment. Our findings indicate that early postnatal treatment with PLX can enhance social abilities and reciprocal social behaviors while reducing repetitive and stereotyped autism-like behaviors, such as excessive grooming and marble burying. RNA sequencing analysis demonstrated that the neuroprotective effects of PLX are associated with reduced glutamatergic synaptic activity. This is further supported by the observation that PLX decreased vesicular glutamate transporter 1 (vGLUT1) expression, a marker of excitatory presynapses in the medial prefrontal cortex (mPFC). Additionally, we observed a reduction in dendritic spines and inhibition of excitatory synaptic transmission in the pyramidal neurons of the BTBR T + Itpr3tf/J (BTBR) mouse mPFC following early postnatal microglial depletion. Our findings highlight the therapeutic potential of PLX and provide valuable insights into the role of glutamatergic synapses in ASD.

Keywords:  Autism spectrum disorder (ASD); Excitatory/inhibitory balance; Glutamatergic synaptic; Medial prefrontal cortex; Microglia; PLX3397

DOI:  https://doi.org/10.1016/j.bbi.2026.106794
Cell Commun Signal. 2026 May 02.

Gas6 restores microglial efferocytosis and limits neuroinflammation in neonatal hypoxic-ischemic encephalopathy by activating MerTK and the PI3K-Rac1 pathway.

Yu Liu, Ayipaxiaguli Kasimu, Yuting Song, Jinke Liu, Chenqin Si, Qiuyi Chen, Yiyun Zhang, Lijian Xie, Danmei Chen, Bing Li.

   AIM: Hypoxic-ischemic encephalopathy is a major cause of neonatal disability and mortality. Its core pathology involves extensive neuronal apoptosis and persistent inflammatory responses. Microglia play a crucial role in maintaining brain homeostasis and promoting injury repair by recognizing and clearing apoptotic neurons. However, the regulatory mechanisms underlying this process remain unclear.
METHOD: This study employed a co-culture model of apoptotic neurons, phagocytic function assays, cytokine analysis, transcriptome sequencing, Gas6 gene knockout and rescue experiments, combined with a mouse model of hypoxic-ischemic brain injury, to elucidate the role of microglia in the phagocytic process and the regulatory function of Gas6.
RESULT: Injured neurons induced an early phase of pro-inflammatory activation and enhanced phagocytic capacity in microglia, followed by a shift towards an anti-inflammatory function. Transcriptome analysis suggested that co-culture with injured neurons activated pathways such as PI3K-AKT and NF-κB in microglia, concomitant with a significant upregulation of Gas6. Furthermore, we found that Gas6 deficiency significantly reduced the phosphorylation level of TAM receptors, leading to impaired downstream PI3K/AKT activation and a marked decrease in Rac1-GTP, thereby suppressing cytoskeletal rearrangement and phagocytic function. In parallel, Gas6-deficient microglia exhibited a sustained pro-inflammatory response, with both their efferocytic capacity and ability to regulate inflammation being significantly compromised. In vivo experiments showed that Gas6-KO mice displayed more severe neurological deficits, increased neuronal apoptosis, and stronger inflammatory responses after HIE. Supplementation with exogenous Gas6 elevated TAM receptor phosphorylation and the PI3K/AKT-Rac1 signaling pathway, partially restoring the phagocytic capacity of microglia.
CONCLUSION: This study demonstrates the important role of the Gas6-TAM-PI3K/AKT-Rac1 signaling axis in modulating microglial efferocytic function and inflammatory state transition. It provides a potential therapeutic strategy for improving HIE prognosis by targeting the regulation of microglial phagocytosis.

Keywords:  Efferocytosis; Growth arrest-specific protein 6; Hypoxic-Ischemic Encephalopathy; MERTK; Microglia; Neuroinflammation; PI3K/AKT signaling pathway

DOI:  https://doi.org/10.1186/s12964-026-02911-2
Acta Pharmacol Sin. 2026 May 07.

TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.

Yan-Yan Li, Jian-Rong Yuan, Jie Tang, Lei Chen, Jun-Chao Wu, Zheng-Hong Qin, Rui Sheng.

  Oxidative stress and inflammation play pivotal roles in the secondary brain injury following intracerebral hemorrhage (ICH). Our previous study on cerebral ischemia showed that TIGAR interacted directly with ATF4, thereby suppressing ATF4-mediated endoplasmic stress. In this study, we investigated whether TIGAR conferred protection against ICH by mitigating oxidative stress and inflammation and the regulatory mechanisms. ICH mouse model was established by microinjection of collagenase VII into the right striatum. Neurological dysfunction score was assessed at 24 h and 72 h post-ICH, and mice were sacrificed and the brains were collected at 72 h post-ICH. We found a significant elevation in TIGAR protein expression in the striatum of ICH mice with increased distribution of TIGAR protein among neurons, microglia and astrocytes. Deletion of TIGAR exacerbated neurological deficits and increased hematoma volume. Conversely, overexpression of TIGAR effectively mitigated neurological deficits, reduced hematoma volume and improved neuronal damage in ICH mice. We demonstrated that TIGAR overexpression significantly attenuated lipid peroxide 4-HNE as well as malondialdehyde content (a lipid oxidation product), while suppressing ROS production. In addition, TIGAR overexpression inhibited NLRP3 inflammasome expression along with caspase-1 cleavage. Moreover, TIGAR overexpression downregulated mRNA levels of inflammatory cytokines IL-1β and IL-6 while impeding microglial transformation into pro-inflammatory M1 phenotype. Intriguingly, TIGAR overexpression exerted inhibitory effects on the expression and activity of ATF4 and NOX4/p22phox involved in intracellular oxidative stress and inflammation regulation. In ICH mice, administration of NOX inhibitor GLX351322 (5 mg·kg-1·d-1, i.p. for 2 days) significantly ameliorated the intracerebral hemorrhage injury exacerbated by TIGAR knockdown. Collectively, we demonstrate upregulation of TIGAR proteins with enhanced distribution among neurons and glial cells post-ICH. TIGAR may alleviate oxidative stress and inflammation by inhibiting the ATF4/NOX4/p22phox signaling pathway, thereby reducing ICH-associated neuronal damage. The role and mechanism of TIGAR in intracerebral hemorrhage injury. TIGAR suppresses the ATF4/NOX4/p22phox axis, thereby reducing the production of reactive oxygen species (ROS), which subsequently alleviates oxidative stress and inflammatory responses to mitigate hemorrhagic injury.

Keywords:  GLX351322; NADPH oxidase 4; TIGAR; inflammation; intracerebral hemorrhage; oxidative stress

DOI:  https://doi.org/10.1038/s41401-026-01751-7
Prog Neurobiol. 2026 May 01. pii: S0301-0082(26)00049-3. [Epub ahead of print]262 102923

Peripheral nerve injury increases the probability of thalamocortical burst firing remotely via microglia-dependent enhancement of tonic inhibition.

Yoshifumi Ueta, Mariko Miyata.

  Burst firing and dysrhythmia of thalamocortical (TC) neurons are involved in central pain. In neuropathic pain, peripheral nerve damage can trigger abnormal firing of distant TC neurons. Here, in the mouse whisker somatosensory thalamus, we aimed to identify the regulatory mechanisms for TC firing induced by an infraorbital nerve cut (IONC). IONC hyperpolarized resting membrane potentials and reduced input resistances of TC neurons. These changes are related to accelerated burst firing and increased spike-frequency adaptation during depolarization. In addition, IONC decreased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by attenuating hyperpolarization-induced voltage sag and shifting the activation potential towards more hyperpolarized potentials. Consistently, IONC reduced the number of rebound spikes after hyperpolarization. We previously reported that IONC-induced neuronal and glial changes in thalamic and brainstem whisker regions are necessary for the development of mechanical hypersensitivity: increased thalamic tonic inhibition via extrasynaptic GABAA receptors and aggregated microglia in the brainstem projecting to the thalamus. We found that genetic ablation of extrasynaptic GABAA receptors in TC neurons prevented IONC-induced changes in membrane properties, and that brain-wide microglial ablation exhibited the same tendency. Whereas brainstem local microglial ablation prevented IONC-induced enhancement of tonic inhibition, thalamic local microglial ablation failed to cause the same phenomenon. Thus, our results suggest that IONC alters distant TC firing via microglial and tonic inhibitory interactions along the ascending pathway. By using these remote mechanisms, peripheral nerve injury may cause central sensitization of neuropathic pain.

Keywords:  Brainstem; Calcium channel; GABA(A) receptor; HCN channel; Neuropathic pain; Somatosensory

DOI:  https://doi.org/10.1016/j.pneurobio.2026.102923
Front Immunol. 2026 ;17 1831161

Ferroptosis-associated myeloid cell heterogeneity and inflammatory amplification following spinal cord injury.

Jian Zhang, Song Wang, Minghang Zhang, Han Qin, Weiliang Wu, Guoliang Chen, Genlong Jiao.

   Background: Spinal cord injury (SCI) causes severe and persistent neurological dysfunction. Ferroptosis has been implicated in multiple neurological disorders, but its contribution to SCI and its relationship to myeloid-cell responses, inflammatory amplification and disturbed iron homeostasis remain unclear.
Methods: We integrated public bulk RNA-sequencing and single-cell RNA-sequencing datasets with experiments in a rat SCI model to define ferroptosis-associated changes across the molecular, cellular and tissue levels. Differential expression, pathway enrichment, co-expression and protein-protein interaction analyses, pseudotime inference and cell-cell communication modelling were used to identify candidate molecules and relevant myeloid subpopulations, followed by qPCR, western blotting and immunofluorescence validation.
Results: Ferroptosis-associated molecular alterations in SCI showed marked temporal dynamics and remained embedded within pathological networks linked to inflammation, oxidative stress and hypoxic responses. Single-cell analysis indicated that these signals were concentrated primarily in myeloid cells, particularly the HMOX1-high M1a and M1b subclusters. Pseudotime and cell-cell communication analyses further suggested that these subpopulations progress along a continuous trajectory towards inflammation-amplifying states and may influence the local microenvironment through MIF, TGFβ, PTN and CD99 signalling. Animal experiments further showed that sustained inflammatory activation occurs in parallel with dysregulation of ferroptosis-associated molecules, accompanied by local myeloid-cell activation and enhanced HMOX1-associated stress responses.
Conclusions: In SCI, ferroptosis-associated signals appear to be concentrated within HMOX1-associated myeloid subpopulations and may be sustained through cell-state reprogramming and intercellular signaling networks. HMOX1 emerges as a candidate hub linking disturbed iron handling, ferroptosis and myeloid inflammatory remodeling.

Keywords:  HMOX1; bioinformatics; ferroptosis; inflammatory microenvironment; macrophages/microglia; spinal cord injury

DOI:  https://doi.org/10.3389/fimmu.2026.1831161