bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–10–25
fourteen papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Microglia and border-associated macrophages play opposite roles in cerebrovascular and leukocyte responses under systemic inflammation in male mice.
  2. Microglial protein kinase CK2 prevents obesity in mice potentially through NLRP3 inflammasome activation.
  3. RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis.
  4. Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.
  5. TSPO-PET binding in vivo reflects increased phagocytic microglia at post mortem in people with frontotemporal dementia.
  6. A microglial basis for fragile X syndrome via impairment of FMRP-regulated lysosomal function.
  7. Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
  8. SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.
  9. Hepatic Orosomucoid 2 aggravates demyelination and drives microglial DAM-like activation.
  10. TIA1 is required for microglial activation in tauopathy.
  11. Protective role of Galectin-3 in prion disease through regulation of microglial PrPSc uptake.
  12. Ifi27l2a Facilitates the Recruitment of Pathogenic T Cells by Retinal Microglia in the Initiation Phase of Experimental Autoimmune Uveoretinitis.
  13. Microglia disulfidptosis contributes to worsening of diabetic retinopathy induced by acute hypoglycemia.
  14. An integrated human forebrain organoid reveals microglia-mediated CD8+ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.
  1. Nat Commun. 2026 09 18. pii: 10946. [Epub ahead of print]17(1):
    Microglia and border-associated macrophages play opposite roles in cerebrovascular and leukocyte responses under systemic inflammation in male mice.
    Ana Rita Brás, Nikolett Lénárt, Damien Levard, Martina Glavan, Ákos Menyhárt, Csaba Cserép, Balázs Pósfai, Eszter Császár, Sai K Reddy Samawar, Clare Pridans, Denis Vivien, Eszter Farkas, Lydia Sorokin, Marina Rubio, Ádám Dénes.
      Microglia closely associate with the vasculature, but their roles in leukocyte trafficking and cerebral blood flow (CBF) during systemic inflammation are unclear. We show that sustained systemic inflammation leads to altered microglia-vascular interactions, leukocyte recruitment to cerebral blood vessels and reduced hypercapnia-induced vasodilation. We find that microglia and border-associated macrophages (BAMs) play distinct roles in these processes: while BAM depletion with clodronate increases leukocyte recruitment, microglia/BAM depletion with PLX5622 and the absence of microglia, but not BAMs in CSF1RΔFIRE/ΔFIRE mice, result in markedly reduced leukocyte recruitment. Supporting this, conditional microglial IL-1 deletion inhibits leukocyte recruitment. Unlike BAM depletion, the absence of microglia impairs hypercapnia-induced vasodilation, while in vivo two-photon imaging reveals microglial IL-1α-dependent interactions between leukocytes and penetrating arteries. Accordingly, reduced hypercapnia-induced vasodilation involves endothelial IL-1R1 and microglial IL-1α. Thus, distinct brain macrophage populations exert opposite effects on leukocyte recruitment and CBF through IL-1 dependent mechanisms in given vascular beds in male mice.
    DOI:  https://doi.org/10.1038/s41467-026-77787-4
  2. Nat Commun. 2026 09 22. pii: 11019. [Epub ahead of print]17(1):
    Microglial protein kinase CK2 prevents obesity in mice potentially through NLRP3 inflammasome activation.
    Ji-Won Lee, Nayoun Kim, Seolsong Kim, Seokjae Park, Hyeri Nam, Younghwan Lee, Seohyeon Hwang, Yeim Lee, Sehee Ha, Wonkeon Koo, Eun-Kyoung Kim, Seong-Woon Yu.
      Protein kinase CK2 plays an important role in the regulation of metabolism and obesity. However, the metabolic role of CK2 and its substrates in the brain remain largely unknown. Here, we show that microglial CK2 is required for metabolic homeostasis through ASC phosphorylation and subsequent NLRP3 inflammasome-mediated interleukin (IL)-18 maturation and release. Mice with microglia-specific, inducible deletion of CK2 regulatory subunit β (CK2β) showed obese phenotypes with weight gain, abnormal glucose homeostasis, and decreased energy expenditure. At the molecular level, CK2 phosphorylated ASC at T154, and this phosphorylation was essential for ASC aggregation and NLRP3 inflammasome activation. Microglial deletion of CK2β decreased central production of IL-18, mirroring the obese phenotypes of mice lacking IL-18 signaling. Our results suggest that the microglial CK2-ASC-NLRP3 axis underlies the central regulation of metabolic homeostasis and prevents obesity through processing and secretion of IL-18. Nevertheless, a gap remains between these molecular mechanistic findings and the observed in vivo behavioral and metabolic phenotypes, highlighting the need for future systems-level analyses to fully delineate the broader substrate landscape of CK2 and to integrate the functional outcomes of CK2 deficiency in microglia with in vivo phenotypes.
    DOI:  https://doi.org/10.1038/s41467-026-77895-1
  3. Nat Commun. 2026 09 21. pii: 11011. [Epub ahead of print]17(1):
    RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis.
    Shuqi Wang, Jian Wang, Madison Hicks, Sushma Bharrhan, Matthew Woolard, Hongyan Guo.
      Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic viral encephalitis, where uncontrolled viral replication and neuroinflammation drive fatal brain injury. Inherited RIPK3 deficiency predisposes humans to severe disease, but the protective mechanism remains unclear. Using single-cell transcriptomics, genetic knockout models, and analysis of viral replication, interferon production, and cell death across neurons, astrocytes, microglia, and myeloid cells, we show that RIPK3 acts as a cell-type-specific molecular switch. RIPK3 scaffolding promotes interferon response and viral control in multiple central nervous system cell types, while RIPK3-dependent apoptosis limits myeloid accumulation. In contrast, RIPK3 kinase activity in astrocytes triggers necroptosis, leading to neuronal loss and lethal neuroinflammation. Genetic or pharmacological inhibition of RIPK3 kinase suppresses astrocyte necroptosis, enhances IFN responses, preserves brain integrity, and improves survival. These findings suggest that selective modulation of RIPK3 signaling may balance antiviral defense with limitation of neuropathology in HSV-1 encephalitis.
    DOI:  https://doi.org/10.1038/s41467-026-77881-7
  4. Adv Sci (Weinh). 2026 Oct 18. e77954
    Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.
    Karthick Chennakesavan, Malaroviyam Samikkannu, Shreyan Gupta, Olasunkanmi Israel Tayo, Arpan Acharya, James J Cai, Siddappa N Byrareddy, Thangavel Samikkannu.
      HIV-associated neurological complications remain a major concern in people living with HIV (PWH), even under effective viral suppression with combination antiretroviral therapy (cART), underscoring unresolved mechanisms driving HIV-related neurodegeneration. To address this gap, we used HIV-1-infected human cerebral organoids (hCOs) containing microglia as a physiologically relevant three-dimensional model of the central nervous system (CNS) and validated key findings in the brain region of simian immunodeficiency virus (SIV)-infected, cART-treated rhesus macaque model. Integrated single-nucleus RNA sequencing with ATAC-seq (multi-omics), identifies cell-type-specific alterations in dual innate immune-driven inflammatory signaling pathways across neural and glial populations in hCOs. Microglia were preferentially infected and activated, initiating IL-17A-mediated cascades involving IFN-γ/STAT1, CEBPB, and NF-κB signaling. These pathways converged with cGAS-STING and Notch-NEURL1 signaling, both associated with neuroinflammation and synaptic dysfunction. cART suppressed viral replication, reduced IL-17A-mediated neuroinflammation, improved mitochondrial function, and restored synaptic gene expression. Collectively, these findings identify dysregulation of IL-17A, STAT1, CEBPB, and cGAS-STING signaling as key molecular drivers of HIV-associated neuroinflammation. They also establish a potential mechanistic link between IL-17A signaling and microglial remodeling, providing a translational framework for the development of CNS-targeted therapies in PWH.
    Keywords:  Combination Antiretroviral Therapy (cART); HIV‐associated neurocognitive disorders (HAND); Human cerebral organoids; Macaque brain; Neuroinflammation; Single nuclei multi‐omics; Synaptic dysfunction
    DOI:  https://doi.org/10.1002/advs.77954
  5. Acta Neuropathol. 2026 Oct 22. pii: 59. [Epub ahead of print]152(1):
    TSPO-PET binding in vivo reflects increased phagocytic microglia at post mortem in people with frontotemporal dementia.
    Davi S Vontobel, Kei Onn Lai, Mehtap Bacioglu, George Nolan, Daniel C Maddison, Amelie Adamski, Julia Goddard, Noah L Shapiro, Harry Crook, Tim Fryer, Young Hong, Sasvi Wijesinghe, Franklin Aigbirhio, Edward Avezov, Kieren S J Allinson, Annelies Quaegebeur, John T O'Brien, James B Rowe, Maria Grazia Spillantini, Maura Malpetti.
      Brain inflammation is a key feature of frontotemporal dementia (FTD). Positron emission tomography (PET) of the 18 kDa translocator protein (TSPO) is widely used as an in vivo proxy for neuroinflammation, but whether the elevated signal reflects microglial, astrocytic or vascular pathology remains controversial, and this has not previously been resolved in FTD using matched ante mortem imaging and post-mortem tissue. We paired ante mortem [11C]PK11195 TSPO-PET with quantitative post-mortem neuropathology in 10 individuals with FTD (5 FTLD-tau, 5 FTLD-TDP) and 5 age- and sex-matched controls, combining CD68 immunohistochemistry across 17 brain regions, multiplex immunofluorescence pairing TSPO with microglial/macrophagic (IBA1, CD68), astrocytic (GFAP) and endothelial (CD31) markers in three frontotemporal cortical regions, and three-dimensional single-cell reconstruction of individual microglia. CD68 area fraction was elevated in FTD relative to controls, predominantly in white matter, and was positively associated with regional TSPO-PET-binding potential across the cohort (β = 8.66, P < 0.001), with comparable slopes in FTLD-tau and FTLD-TDP. Total tissue TSPO-area fraction was likewise increased in FTD and tracked regional PET binding in two independently processed slide sets. Of the four cell-type markers, only the CD68-TSPO co-localised fraction was positively associated with the PET signal (β = +0.0041, P = 0.015, PFDR = 0.062), with null or negative associations for IBA1, GFAP and CD31. At single-cell resolution, IBA1+ microglia that were also CD68+ carried more absolute TSPO and were larger than CD68- microglia, without an increase in the TSPO fraction of cell volume. The elevated TSPO-PET signal in FTD, therefore, likely reflects an increased burden of CD68+ phagocytic microglia rather than TSPO expression in other cell types, supporting TSPO-PET as a microglial-burden biomarker across both FTLD-tau and FTLD-TDP.
    Keywords:  CD68; Frontotemporal dementia; Microglia; Neuroinflammation; Post-mortem neuropathology; TSPO–PET
    DOI:  https://doi.org/10.1007/s00401-026-03103-5
  6. Mol Psychiatry. 2026 Oct 17.
    A microglial basis for fragile X syndrome via impairment of FMRP-regulated lysosomal function.
    Heng Li, Jennifer Ja-Yoon Choi, Eric J Huang, Baoji Xu.
      Silencing of the FMRP-encoding FMR1 gene results in fragile X syndrome (FXS), the most common inheritable intellectual disability and autism. FMRP regulates various neuronal functions but clinical trials targeting neurons have failed, suggesting unrecognized disease mechanisms. We find that mice with selective Fmr1 deletion in microglia exhibit audiogenic seizures (AGS) and parvalbumin (PV) neuron loss, recapitulating two key phenotypes observed in FXS (Fmr1-/y) mice. By combining snRNA-Seq and RNA immunoprecipitation, we identify several lysosomal mRNAs as FMRP binding targets. FMRP promotes lysosomal protein expression and its deficiency disrupts lysosomal function in microglia. Notably, FMRP depletion reduces Grn-encoded secretory progranulin and increases PV neuron apoptosis in immature brains. PV neuron density is decreased similarly in Grn+/-, Fmr1-/y, and Grn+/-;Fmr1-/y mice, and progranulin overexpression rescues AGS and PV neuron loss in Fmr1-/y mice. Thus, our study identifies microglia and progranulin as critical regulators of FXS pathogenesis and potential targets for FXS therapy.
    DOI:  https://doi.org/10.1038/s41380-026-03927-3
  7. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2610766123
    Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
    Sara Bermudez, Jung-Hyun Choi, Niaz Mahmood, Jacob W Vogel, Hashem Almousa, Ziying Huang, Sung-Hoon Kim, Vivian Yuchan Zhu, Linqiao Zhou, Diana Casas-Antillon, Moein Yaqubi, Danielle Cozachenco, Jo Anne Stratton, Oskar Hansson, Luke Healy, Argel Aguilar-Valles, Nahum Sonenberg.
      In Alzheimer's disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are elevated in AD and correlate with markers of microglial reactivity and disease progression. Using linear regression analysis, we found that elevated CSF 4E-BP1 levels strengthen the association between soluble TREM2 levels and neurodegeneration in amyloid-positive individuals. To investigate the underlying mechanism, we performed in vitro experiments demonstrating that amyloid-β inactivated 4E-BP1 in murine microglia. The mTOR-mediated inactivation is highly dependent on Spleen Tyrosine Kinase (SYK) signaling and repeated exposure to amyloid-β impaired this process, whereas prolonged exposure increased 4E-BP1 levels in microglia. Deletion of 4E-BP1/2 resulted in increased mitochondrial mass and oxidative phosphorylation, reduced pro-inflammatory signaling, and protected microglia from amyloid-induced apoptosis. Thus, impaired 4E-BP1 inactivation-due to reduced mTOR signaling or excess 4E-BP1-disrupts immune resolution, leading to metabolic exhaustion and microglial cell death. We identify the SYK-mTORC1-4E-BP1 signaling axis as a key regulator of microglial mitochondrial biogenesis and immune resolution in AD.
    Keywords:  Alzheimer’s disease; inflammation; mTOR; microglia
    DOI:  https://doi.org/10.1073/pnas.2610766123
  8. J Neuroinflammation. 2026 Jul 22. pii: 347. [Epub ahead of print]23(1):
    SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.
    Yu-Ge Zhang, Shi-Yao Li, Yi-Zhen Hu, Yi Ding, Yu-Tong Zhang, Hui-Wen Zhang, Yong-Jie Zhang, Lu Xu, Zhi-Yuan Zhang, Lei Li.
       BACKGROUND: Microglial metabolic dysfunction is increasingly recognized as a key driver of neuroinflammation in Alzheimer's disease (AD). However, the specific metabolic regulators linking lipid metabolism to pathological activation remain poorly defined.
    METHODS: We performed integrative transcriptomic analysis on four human AD brain datasets to identify core metabolic hubs. Sprouty homolog 1 (SPRY1) expression was examined in human post-mortem tissues, and its functional role was validated in primary microglia, Drosophila, and APP/PS1-21 mice using genetic knockdown, behavioral assays, and histological analysis. Moreover, we employed co-immunoprecipitation, mass spectrometry, and metabolic flux assays to elucidate the underlying pathways.
    RESULTS: We identified SPRY1 as a key hub gene upregulated in the hippocampus of AD patients and mouse models. SPRY1 was predominantly expressed in plaque-associated microglia, and specifically correlated with advancing age, Aβ load and Braak stage. Functionally, microglial SPRY1 knockdown enhanced Aβ phagocytosis, reduced pro-inflammatory cytokines, and protected neurons from Aβ-induced damage in vitro. In vivo, glial-specific knockdown of the SPRY1 homolog sty rescued cognitive and motor deficits in AD flies, while microglia-specific knockdown in mice reduced amyloidosis and neuroinflammation. Mechanistically, SPRY1 acted as a metabolic switch by retaining fatty acid transport protein 3 (FATP3) on the endoplasmic reticulum (ER). This interaction blocked FATP3 translocation to mitochondria, thereby reducing fatty acid oxidation (FAO) and promoting lipid droplet (LD) accumulation, which drives a microglial pro-inflammatory phenotype.
    CONCLUSIONS: This study unveils a novel SPRY1-FATP3 retention mechanism that links impaired fatty acid metabolism to neuroinflammation. Targeting this axis represents a promising strategy to reprogram microglial metabolism and provide neuroprotection in AD.
    Keywords:  Alzheimer’s disease; FATP3; Fatty acid oxidation; Lipid droplet; Lipid metabolism; Microglia; Neuroinflammation; SPRY1
    DOI:  https://doi.org/10.1186/s12974-026-03949-2
  9. J Neuroinflammation. 2026 Jul 28. pii: 353. [Epub ahead of print]23(1):
    Hepatic Orosomucoid 2 aggravates demyelination and drives microglial DAM-like activation.
    Hanqi Bi, Yuzi Xu, Min Xu, Ni Zhang, Xiaofeng Li, Chao Chen, Minghua Zheng, Yan Lu, Wenjing Shi, Qian Wang.
       INTRODUCTION: Demyelination is a central pathological feature of white matter injury (WMI). Emerging evidence suggests that hepatokines act as systemic regulators of brain pathology, raising the possibility that liver-derived signals contribute to WMI. Here, we investigated whether hepatokine Orosomucoid 2 (ORM2) aggravates demyelination through liver-brain communication by modulating disease-associated microglia (DAM)-like activation in WMI.
    METHODS: ORM2 expression was assessed in the cuprizone (CPZ) demyelination model using RNA sequencing, quantitative PCR, western blotting, and immunofluorescence. The functional role of ORM2 in WMI was examined using ORM2 knockout mice, hepatocyte-specific ORM2 transgenic mice, and hepatocyte-targeted ORM2 knockdown strategies, combined with behavioral analyses and histological evaluation of myelin integrity. Transcriptomic profiling, lipid staining, and microglial phenotyping were performed to characterize DAM-associated responses.
    RESULTS: CPZ-induced demyelinating challenge was accompanied by robust hepatic ORM2 induction and increased cerebral ORM2 protein accumulation. Flag-tagged ORM2 tracing showed that hepatocyte-derived ORM2 could be detected in the injured brain after CPZ-induced white matter injury. ORM2 deficiency alleviated, whereas hepatocyte-specific ORM2 overexpression exacerbated, demyelination and behavioral deficits. Hepatocyte-targeted knockdown of ORM2 reduced cerebral ORM2 accumulation and mitigated white matter pathology, supporting a peripheral contribution of hepatic ORM2 to WMI. Transcriptomic and histological analyses revealed that ORM2 promoted inflammatory and DAM-like microglial programs. Mechanistically, ORM2 promoted activation of the SYK-PLCγ2 signaling axis, thereby driving DAM-like activation, lipid-associated dysregulation, and myelin loss.
    CONCLUSIONS: Our findings identify hepatic ORM2 as a pro-inflammatory hepatokine that aggravates WMI through liver-brain communication. By enhancing SYK-PLCγ2 signaling and driving DAM-like microglial activation, ORM2 links peripheral hepatic stress to central demyelination, highlighting hepatic ORM2 as a potential therapeutic target for white matter disorders.
    Keywords:  Demyelination; Disease-associated microglia (DAM); Liver-brain communication; Orosomucoid 2 (ORM2); SYK-PLCγ2 signaling
    DOI:  https://doi.org/10.1186/s12974-026-03988-9
  10. Cell Rep. 2026 Oct 22. pii: S2211-1247(26)01278-7. [Epub ahead of print]45(11): 118199
    TIA1 is required for microglial activation in tauopathy.
    Chelsea J Webber, Sophie J F van der Spek, Anna Lourdes Cruz, Sambhavi Puri, Yiren Shao, Cheng Zhang, Jacqueline T M Aw, Georgia-Zeta Papadimitriou, Rebecca Roberts, Kiki Jiang, Thuc Nhan Tran, Lushuang Zhang, Alexandria Taylor, Zihan Wang, Katarnut Tobunluepop, Madhav Ellini, Jacob Porter, Ionnis Sotiropoulos, Andrew Emili, Joana Silva, Hu Li, Benjamin Wolozin.
      The RNA-binding protein T cell intracellular antigen-1 (TIA1) regulates cellular stress responses and tau pathology, key contributors to the pathophysiology of tauopathies, including Alzheimer's disease (AD). TIA1 acts in peripheral monocytes to inhibit inflammation, but its function in central microglia, critical to neuroinflammation and disease progression, remains unknown. Here, we crossed TIA1 microglial conditional knockout (cKO) mice (using a Cx3cr1-driven Cre element) with the PS19 P301S MAPT mouse model of tauopathy and demonstrated that TIA1 promotes microglial activation, with a corresponding suppression of microglia activation upon TIA1cKO. We observe striking reductions in cytokine (Tnf-α and Il-1β) and sensome markers (Clec7a, Trem2, and Itgax); importantly, these reductions were accompanied by decreases in tau pathology. Proteomic analyses show TIA1 interaction with the microglial proteins C1Q, previously implicated in microglial activation. These results position TIA1 as a regulator of neuroinflammation and tauopathy in CX3CR1-expressing myeloid cells, including microglia, with potentially divergent functions in central versus peripheral immune compartments.
    Keywords:  Alzheimer’s disease; Bin1; C1Q; CP: neuroscience; DAM microglia; IFN-gamma; RNA sequencing; TIA1; inflammation; microglia; tau pathology
    DOI:  https://doi.org/10.1016/j.celrep.2026.118199
  11. Brain Pathol. 2026 Oct 22. pii: e70161. [Epub ahead of print]
    Protective role of Galectin-3 in prion disease through regulation of microglial PrPSc uptake.
    Natallia Makarava, Tarek Safadi, Narayan P Pandit, Olga Mychko, Olga Bocharova, Alexey Shevelkin, Kara Molesworth, Marta M Lipinski, Ilia V Baskakov.
      Microglia constitute a major innate defense mechanism against prion infection; however, the molecular pathways regulating microglial responses during disease progression remain incompletely understood. Galectin-3 (Gal3), a β-galactoside-binding lectin associated with reactive microglia in multiple neurodegenerative disorders, has been implicated in phagocytosis, inflammatory signaling, and lysosomal homeostasis. Here, we investigated the role of Gal3 in prion disease pathogenesis using prion-infected mice. Gal3 expression was undetectable in healthy brain but became upregulated beginning at late preclinical stages, increasing with disease progression. Gal3 localized predominantly to a subpopulation of reactive IBA1-positive microglia, particularly within the thalamus, and inversely correlated with expression of the homeostatic microglial markers P2Y12 and TMEM119, consistent with acquisition of a reactive phenotype. Microglia engaged in neuronal envelopment displayed elevated Gal3 expression during terminal disease. Constitutive deletion of Gal3 significantly accelerated clinical disease progression without altering total PrPSc accumulation, reactive gliosis, neuronal envelopment, or overall microglial and astrocytic activation. However, Gal3 deficiency markedly reduced microglial uptake of PrPSc, resulting in a lower intracellular-to-extracellular PrPSc ratio, supporting a role for Gal3 in phagocytic sequestration of prions. In contrast, Gal3 deficiency did not impair lysosomal activity, lysosomal membrane integrity, or expression of genes involved in lysosomal repair pathways. Likewise, selective inhibition of autophagy in myeloid cells exerted only minor effects on disease progression. Collectively, these findings identify Gal3 as a sensitive marker of reactive microglia that contributes to microglial uptake of PrPSc and exerts a protective role during prion disease progression.
    Keywords:  Beclin 1; Galectin 3; autophagy; lysosomes; neuroinflammation; phagocytosis; prion diseases; prions; reactive microglia
    DOI:  https://doi.org/10.1111/bpa.70161
  12. Glia. 2026 Dec;pii: e70247. [Epub ahead of print]74(12): e70247
    Ifi27l2a Facilitates the Recruitment of Pathogenic T Cells by Retinal Microglia in the Initiation Phase of Experimental Autoimmune Uveoretinitis.
    Wenna Gao, Pucheng Wu, Kunpeng Xie, Pengyi Zhou, Bo Jin, Haiyan Zhu, Fuzhen Li, You Wang, Bo Lei, Xuemin Jin, Liping Du.
      The mechanisms by which pathogenic T cells enter the immune-privileged retina at the onset of uveitis remain unclear. To identify regulatory targets that promote retinal inflammation, we established an experimental autoimmune uveoretinitis (EAU) model by immunizing C57BL/6J mice with IRBP651-670 and dynamically evaluated retinal inflammation after induction; fundus lesions were prominent, with the first 14 days representing the initiation phase, Days 14-28 the amplification phase, Days 28-35 the peak phase, and Days 35-42 the regression phase. We characterized retinal cellular alterations from the pre-inflammatory stage to the peak stage using single-cell transcriptomic analysis, and found that retinal immune cells changed in parallel with EAU severity, while immune-cell interactions were strongest on Day 14, especially between microglia and T cells through multiple chemokine-related pathways. We then identified key cell populations and candidate targets through integrated analyses and functional validation, and Ifi27l2a emerged as a core gene associated with inflammatory and immune responses in retinal microglia on Day 14. In vitro knockdown of Ifi27l2a in LPS-activated BV-2 cells reduced inflammatory mediator production and abolished Th1/Th17 induction. In vivo targeting of Ifi27l2a attenuated EAU severity and restored the balance of T-cell subsets. These findings indicate that microglia are highly activated before retinal inflammation becomes prominent and that Ifi27l2a regulates this early pathogenic process.
    DOI:  https://doi.org/10.1002/glia.70247
  13. J Biol Chem. 2026 Oct 22. pii: S0021-9258(26)02548-2. [Epub ahead of print] 113676
    Microglia disulfidptosis contributes to worsening of diabetic retinopathy induced by acute hypoglycemia.
    Xueying Lou, Zhaozhao Gu, Min Ji, Yuxin Luo, Tianzhen He, Lingling Zhao, Aimin Sang, Ying Yu.
      The early worsening of diabetic retinopathy (DR) is associated with rapid declines in blood glucose levels during diabetes treatment, yet its pathogenesis remains poorly understood. This study aims to investigate the role of acute hypoglycemia (AH) in microglial disulfidptosis and the underlying mechanisms during DR progression. Using single-cell sequencing, we identified SLC7A11high microglia. Glucose deprivation further upregulated SLC7A11 expression in microglia, leading to excessive cystine uptake, NADPH depletion, and disulfide stress, which also activated Rac1-WRC signaling, driving F-actin contraction and plasma membrane detachment, ultimately inducing disulfidptosis and elevating pro-inflammatory cytokine levels in microglia. In vivo, SLC7A11 was highly expressed by retinal microglia in AH mice, and AH exacerbated retinal vascular leakage, structural disorganization, and microglial cell death in the retinas of AH mice. Collectively, these findings suggest that glucose deprivation triggers microglial disulfidptosis, providing a potential mechanism by which hypoglycemia exacerbates early DR deterioration, and identifying possible therapeutic targets for intervention.
    Keywords:  Acute hypoglycemia; Diabetic retinopathy; Disulfidptosis; Microglia
    DOI:  https://doi.org/10.1016/j.jbc.2026.113676
  14. Elife. 2026 Oct 20. pii: RP111730. [Epub ahead of print]15
    An integrated human forebrain organoid reveals microglia-mediated CD8+ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.
    Yilin Feng, Feifei Yu, Jiyuan Tang, Honghui Zheng, Zitian Wang, Shaohua Ma.
      Genetic evidence implicates immune dysfunction in Alzheimer's disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates human induced pluripotent stem cell-derived microglia and CD8+ T cells to reconstitute multicellular AD pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-β clearance and neuronal maturation but also drive inflammatory activation and recruit CD8+ T cells through CCL4/5 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron-immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models.
    Keywords:  Alzheimer's disease; CCL5-CCR5 signaling; CD8+ T cells; microglia; neuroinflammation; neuroscience; organoid; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.111730
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