Glia最新文献

{"title":"Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis","authors":"Anirudhya Lahiri,&nbsp;Savannah G. Sims,&nbsp;Jessica A. Herstine,&nbsp;Alicia Meyer,&nbsp;Micah J. Marshall,&nbsp;Ishrat Jahan,&nbsp;Subhodip Adhicary,&nbsp;Allison M. Bradbury,&nbsp;Gordon P. Meares","doi":"10.1002/glia.70067","DOIUrl":"10.1002/glia.70067","url":null,"abstract":"<p>Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated <i>EIF2B5</i> mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2273-2288"},"PeriodicalIF":5.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial Bmal1 Contributes to Diurnal Physiology and Retinal Homeostasis","authors":"Charles W. Pfeifer,&nbsp;Andrea Santeford,&nbsp;Rajendra S. Apte","doi":"10.1002/glia.70061","DOIUrl":"10.1002/glia.70061","url":null,"abstract":"<div>\u0000 \u0000 <p>Circadian rhythms govern various physiological processes, including innate and adaptive immune responses. Microglia, the sentinels of the central nervous system (CNS), mediate synaptic remodeling and local immune responses that contribute to tissue homeostasis. Recent studies have uncovered that microglial surveillance behavior and cytokine production exhibit rhythmicity. Furthermore, disruption of clock gene expression in microglia impairs phagocytic capacity, metabolism, and inflammatory responses, suggesting that their dynamic functions are regulated in part by circadian rhythms. Given the growing recognition of circadian dysregulation in disease pathophysiology, elucidating molecular mechanisms of microglial chronobiology may reveal novel therapeutic strategies to resynchronize circadian rhythms with components of the immune system. Homeostatic rhythms and the implications of their disruption have yet to be explored in microglia that reside within the neurosensory retina, a tissue in the back of the eye that initiates visual transduction and relays photic information to the brain. In this study, we demonstrate that retinal microglia express rhythms in clock gene expression, morphology, and inflammatory markers that rely on the clock gene <i>Bmal1.</i> We also find that loss of <i>Bmal1</i> in microglia is associated with a decline in retinal health and behavioral dysfunction in the mouse. Lastly, we demonstrate that <i>Bmal1</i> deficiency also induces a senescent, disease-associated phenotype in microglia and transcriptomic reprogramming in the retinal parenchyma. These findings suggest that diurnal clock rhythms regulate microglia physiology within the retinal niche and contribute to homeostatic maintenance of the local tissue environment.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2206-2220"},"PeriodicalIF":5.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Abstracts","authors":"","doi":"10.1002/glia.70039","DOIUrl":"https://doi.org/10.1002/glia.70039","url":null,"abstract":"","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 S1","pages":"E5-E232"},"PeriodicalIF":5.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chair Index","authors":"","doi":"10.1002/glia.70040","DOIUrl":"https://doi.org/10.1002/glia.70040","url":null,"abstract":"","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 S1","pages":"E1412-E1414"},"PeriodicalIF":5.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poster Abstracts","authors":"","doi":"10.1002/glia.70038","DOIUrl":"https://doi.org/10.1002/glia.70038","url":null,"abstract":"","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 S1","pages":"E233-E1364"},"PeriodicalIF":5.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 73, Issue 8","authors":"Binri Sasaki,&nbsp;Momo Oishi,&nbsp;Tomoka Aoki,&nbsp;Mai Hyodo,&nbsp;Chinami Onchi,&nbsp;Nanako Yamada,&nbsp;Hitomi Misawa,&nbsp;Momona Yamada,&nbsp;Chikako Hayashi,&nbsp;Kiyotoshi Sekiguchi,&nbsp;Keisuke Hamada,&nbsp;Yuji Yamada,&nbsp;Yamato Kikkawa,&nbsp;Motoyoshi Nomizu,&nbsp;Nobuharu Suzuki","doi":"10.1002/glia.24558","DOIUrl":"https://doi.org/10.1002/glia.24558","url":null,"abstract":"<p>Cover Illustration: Oligodendrocyte binds to laminin on the perivascular basement membrane in the murine cortex at the age of postnatal day 16 (red: CC-1; green: laminin alpha-2; blue: DAPI). (See Sasaki, B., et al, https://doi.org/10.1002/glia.70027)\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drebrin Upregulation Regulates Astrocyte Polarization and Supports Tissue Recovery After Spinal Cord Injury in Mice","authors":"Barbora Smejkalová,&nbsp;Marta Ornaghi,&nbsp;Kateřina Štěpánková,&nbsp;Juliane Schiweck,&nbsp;Lucia Machová Urdzíková,&nbsp;Robert Huelse,&nbsp;Susanne Mueller,&nbsp;Philipp Boehm-Sturm,&nbsp;Jessica C. F. Kwok,&nbsp;James Fawcett,&nbsp;Kai Murk,&nbsp;Britta J. Eickholt,&nbsp;Pavla Jendelová","doi":"10.1002/glia.70048","DOIUrl":"10.1002/glia.70048","url":null,"abstract":"<p>Spinal cord injury (SCI) results in significant disruption of nerve fibers responsible for transmitting signals between the brain and body, often leading to partial or complete motor, sensory, and autonomic dysfunction below the injury site. Astrocytes are an important component in scar formation, crucial for suppression of injury propagation, effective wound healing, and the regulation of neuronal plasticity. Here, we identify the role of the actin-binding protein Drebrin (DBN) in reactive astrogliosis following SCI. SCI induces the upregulation of DBN in astrocytes, which controls immediate injury containment but also the long-term preservation of tissue integrity and healing in the spinal cord. DBN knockout results in enlarged spinal cord lesions, increased immune cell infiltration, and neurodegeneration. Mechanistically, DBN loss disrupts the polarization of scar border-forming astrocytes, leading to impaired encapsulation of the injury. In summary, DBN serves as a pivotal regulator of SCI outcome by modulating astrocytic polarity, which is essential for establishing a protective barrier confining the lesion site.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 9","pages":"1910-1924"},"PeriodicalIF":5.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Volume Regulation and Electrophysiology of Astrocytes In Situ in a Mouse Model for Megalencephalic Leukoencephalopathy With Subcortical Cysts","authors":"Sven Kerst,&nbsp;Nina Meesters,&nbsp;Tim S. Heistek,&nbsp;Marjo S. van der Knaap,&nbsp;Huibert D. Mansvelder,&nbsp;Rogier Min","doi":"10.1002/glia.70047","DOIUrl":"10.1002/glia.70047","url":null,"abstract":"<p>Electrical signaling, driven by ion fluxes between intra- and extracellular compartments, is central to brain functioning. Astrocytes provide crucial support by maintaining the homeostasis of water and ions in the brain. This is disrupted in the leukodystrophy Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC). Studies on cultured primary astrocytes and other isolated cell lines point to a central defect in astrocyte volume regulation in MLC. However, cell culture severely alters the properties and polarity of astrocytes. Therefore, whether astrocytes in the intact MLC brain exhibit aberrant physiology related to water and ion homeostasis remains unknown. To investigate astrocyte physiology in intact astrocytes, we performed experiments in acute brain slices from a validated MLC mouse model, the <i>Glialcam</i>-null mouse. We combined viral sensor delivery with two-photon microscopy to study astrocyte volume regulation and associated chloride dynamics. Cortical <i>Glialcam</i>-null astrocytes showed normal intracellular chloride dynamics but reduced volume recovery upon potassium-induced cell swelling. Whole-cell patch-clamp recordings revealed a modestly depolarized resting membrane potential and slower glutamate uptake in <i>Glialcam</i>-null astrocytes. Gap junction coupling of the astrocyte syncytium was modestly reduced, but it remained sufficient to preserve functional electrical isopotentiality. In conclusion, our findings confirm that the previously observed disturbance of astrocyte volume regulation observed in cultured cells is also observed in intact astrocytes in situ, and we uncover additional changes in astrocyte electrophysiological properties. These findings support the concept that dysfunctional astrocyte volume regulation is central to the MLC disease mechanism.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 9","pages":"1899-1909"},"PeriodicalIF":5.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 73, Issue 7","authors":"Joseph Matthew Holden,&nbsp;Andrew M. Boal,&nbsp;Lauren Katie Wareham,&nbsp;David John Calkins","doi":"10.1002/glia.24556","DOIUrl":"https://doi.org/10.1002/glia.24556","url":null,"abstract":"<p>Cover Illustration: Stochastically labeled astrocytes (cyan) and Müller glia (magenta) contacting blood vessels (orange) and neural cell bodies and axons bundles (green) in a mouse retina. (See Holden, JM, et al, https://doi.org/10.1002/glia.70022)\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelin Lipid Composition in the Central Nervous System Is Regionally Distinct and Requires Mechanistic Target of Rapamycin Signaling","authors":"Marie L. Mather,&nbsp;Angelina V. Evangelou,&nbsp;Jennifer N. Bourne,&nbsp;Wendy B. Macklin,&nbsp;Teresa L. Wood","doi":"10.1002/glia.70042","DOIUrl":"10.1002/glia.70042","url":null,"abstract":"<p>Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 9","pages":"1841-1859"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}