{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:48:29Z","timestamp":1783428509929,"version":"3.54.6"},"reference-count":106,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Tuberculosis (TB), caused by <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (Mtb) infection, is a chronic inflammatory disease. Although typically associated with inflammation of the lungs and other peripheral tissues, increasing evidence has uncovered neurological consequences attributable to Mtb infection. These include deficits in memory and cognition, increased risk for neurodegenerative disease, and progressive neuropathology. Although the neurological effects of the disease, without CNS infection, have been characterized, the mechanism of neurotoxicity is unknown. We hypothesized that alterations to the blood-brain barrier (BBB) allows peripheral immune cells to enter the brain, initiating a neuroinflammatory response. To test this hypothesis, guinea pigs were exposed by aerosol to a laboratory and a clinical Mtb strain for 15 days. Following Mtb infection, proteins critical to BBB function, including claudin V and collagen IV, are modulated without evidence of bacterial dissemination to the brain. This is correlated with increased contact of astrocytic processes to vessels in the brain, as well as increased expression of the water channel protein aquaporin 4 (AQP4) on endfeet. Upon further investigation, we discovered the potential role of glial reactivity, which is increased following infection with both bacterial strains, in the progression of BBB changes and, ultimately, the permeability of peripheral immune cells into the brain. Through these data, we have obtained a preliminary understanding of the mechanisms of cellular stress in the brain following pulmonary Mtb infection which should be further investigated in future studies.<\/jats:p>","DOI":"10.1371\/journal.pone.0307577","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T18:27:09Z","timestamp":1735669629000},"page":"e0307577","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Immune cell infiltration and modulation of the blood-brain barrier in a guinea pig model of tuberculosis: Observations without evidence of bacterial dissemination to the brain"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1402-2801","authenticated-orcid":true,"given":"Amanda S.","family":"Latham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8897-6966","authenticated-orcid":true,"given":"Charlize E.","family":"Geer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Ackart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin N.","family":"Weninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2422-5711","authenticated-orcid":true,"given":"Chase C.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2548-8826","authenticated-orcid":true,"given":"Brendan K.","family":"Podell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall J.","family":"Basaraba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-2712","authenticated-orcid":true,"given":"Julie A.","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"pone.0307577.ref001","unstructured":"Organization WH. Global tuberculosis report 2021. 2021 978-92-4-003702-1."},{"issue":"1","key":"pone.0307577.ref002","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S2213-2600(19)30418-7","article-title":"WHO global progress report on tuberculosis elimination","volume":"8","author":"E Harding","year":"2020","journal-title":"The Lancet Respiratory Medicine"},{"key":"pone.0307577.ref003","unstructured":"R F, Glaziou P, Harris JB, Date A, Floyd K, Kasaeva T. Epidemiology of Tuberculosis and Progress Toward Meeting Global Targets\u2014Worldwide 2019. MMWR Morb Mortal Wkly Reports. 2021;(1545-861X (Electronic))."},{"issue":"10","key":"pone.0307577.ref004","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/cid\/ciy718","article-title":"Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction","volume":"68","author":"KR Robertson","year":"2019","journal-title":"Clin Infect Dis"},{"issue":"2","key":"pone.0307577.ref005","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1017\/S0317167100049027","article-title":"Immunological Associations in Familial and Non-Familial Alzheimer Patients and Their Families","volume":"21","author":"MF Frecker","year":"1994","journal-title":"Canadian Journal of Neurological Sciences \/ Journal Canadien des Sciences Neurologiques"},{"issue":"6","key":"pone.0307577.ref006","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1177\/1533317515577186","article-title":"Increased risk of dementia among patients with pulmonary tuberculosis: a retrospective population-based cohort study","volume":"30","author":"YH Peng","year":"2015","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"8","key":"pone.0307577.ref007","doi-asserted-by":"crossref","first-page":"e2883","DOI":"10.1097\/MD.0000000000002883","article-title":"Association Between Tuberculosis and Parkinson Disease: A Nationwide, Population-Based Cohort Study","volume":"95","author":"CH Shen","year":"2016","journal-title":"Medicine (Baltimore)"},{"key":"pone.0307577.ref008","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2023.1157652","article-title":"Gliosis, misfolded protein aggregation, and neuronal loss in a guinea pig model of pulmonary tuberculosis","volume":"17","author":"AS Latham","year":"2023","journal-title":"Frontiers in Neuroscience"},{"key":"pone.0307577.ref009","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia Function in the 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Line","volume":"24","author":"ME Clementi","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"11","key":"pone.0307577.ref013","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics13111779","article-title":"Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview","volume":"13","author":"SR Archie","year":"2021","journal-title":"Pharmaceutics"},{"key":"pone.0307577.ref014","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2020.00764","article-title":"Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders","volume":"14","author":"M Xiao","year":"2020","journal-title":"Frontiers in Neuroscience"},{"issue":"3","key":"pone.0307577.ref015","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s10545-013-9608-0","article-title":"Blood\u2013brain barrier structure and function and the challenges for CNS drug delivery","volume":"36","author":"NJ 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but dispensable for initiation of its assembly during early development","volume":"131","author":"E P\u00f6schl","year":"2004","journal-title":"Development"},{"issue":"5725","key":"pone.0307577.ref022","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.1109418","article-title":"Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly","volume":"308","author":"DB Gould","year":"2005","journal-title":"Science"},{"issue":"14","key":"pone.0307577.ref023","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1056\/NEJMoa053727","article-title":"Role of COL4A1 in small-vessel disease and hemorrhagic stroke","volume":"354","author":"DB Gould","year":"2006","journal-title":"N Engl J Med"},{"issue":"3","key":"pone.0307577.ref024","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.nbd.2005.09.007","article-title":"In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9\/TIMP-1 ratio and increased collagen type IV degradation","volume":"21","author":"J Sellner","year":"2006","journal-title":"Neurobiology of Disease"},{"issue":"1","key":"pone.0307577.ref025","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.brainres.2006.09.093","article-title":"Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation","volume":"1125","author":"J Sellner","year":"2006","journal-title":"Brain Research"},{"key":"pone.0307577.ref026","doi-asserted-by":"crossref","first-page":"575598","DOI":"10.3389\/fphys.2020.575598","article-title":"Increased Immunosignals of Collagen IV and Fibronectin Indicate Ischemic Consequences for the Neurovascular Matrix Adhesion Zone in Various Animal Models and Human Stroke Tissue","volume":"11","author":"D Michalski","year":"2020","journal-title":"Front 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Acquire Stem Cell Properties in Response to Sonic Hedgehog","volume":"12","author":"S Sirko","year":"2013","journal-title":"Cell Stem Cell"},{"issue":"8","key":"pone.0307577.ref034","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1172\/JCI91301","article-title":"Astrocytic tight junctions control inflammatory CNS lesion pathogenesis","volume":"127","author":"S Horng","year":"2017","journal-title":"J Clin Invest"},{"issue":"1","key":"pone.0307577.ref035","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/s41598-018-37419-4","article-title":"Astrocytic endfeet re-cover blood vessels after removal by laser ablation","volume":"9","author":"H Kubotera","year":"2019","journal-title":"Scientific Reports"},{"issue":"9","key":"pone.0307577.ref036","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.celrep.2015.07.051","article-title":"Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS","volume":"12","author":"B Schreiner","year":"2015","journal-title":"Cell Reports"},{"issue":"2","key":"pone.0307577.ref037","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/glia.23908","article-title":"Astrocytes are necessary for blood\u2013brain barrier maintenance in the adult mouse brain","volume":"69","author":"BP Heithoff","year":"2021","journal-title":"Glia"},{"issue":"3","key":"pone.0307577.ref038","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.neuint.2008.12.002","article-title":"A new blood\u2013brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes","volume":"54","author":"S Nakagawa","year":"2009","journal-title":"Neurochemistry International"},{"issue":"6","key":"pone.0307577.ref039","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1038\/s41380-022-01511-z","article-title":"The blood-brain barrier in aging and neurodegeneration","volume":"27","author":"EG Knox","year":"2022","journal-title":"Molecular Psychiatry"},{"key":"pone.0307577.ref040","doi-asserted-by":"crossref","DOI":"10.3389\/fragi.2023.1244149","article-title":"Biological agents and the aging brain: glial inflammation and neurotoxic signaling","volume":"4","author":"AS Latham","year":"2023","journal-title":"Frontiers in Aging"},{"issue":"1","key":"pone.0307577.ref041","doi-asserted-by":"crossref","first-page":"16031","DOI":"10.1038\/s41598-017-16250-3","article-title":"Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis","volume":"7","author":"S Brilha","year":"2017","journal-title":"Scientific Reports"},{"issue":"1","key":"pone.0307577.ref042","first-page":"30","article-title":"Assessment of Blood-Brain Barrier Integrity in Tuberculous Meningitis Using Dynamic Contrast-Enhanced MR Perfusion","volume":"31","author":"S Kumar","year":"2021","journal-title":"Indian J Radiol Imaging"},{"issue":"3","key":"pone.0307577.ref043","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.pscychresns.2008.04.003","article-title":"Blood\u2013brain barrier permeability in Alzheimer\u2019s disease: a case\u2013control MRI study","volume":"171","author":"JM Starr","year":"2009","journal-title":"Psychiatry Research: Neuroimaging"},{"key":"pone.0307577.ref044","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2020.593026","article-title":"Blood\u2013Brain Barrier Leakage Is Increased in Parkinson\u2019s Disease","volume":"11","author":"S Al-Bachari","year":"2020","journal-title":"Frontiers in Physiology"},{"issue":"2","key":"pone.0307577.ref045","doi-asserted-by":"crossref","first-page":"BSR20193629","DOI":"10.1042\/BSR20193629","article-title":"Peripheral inflammation promotes brain tau transmission via disrupting blood\u2013brain barrier","volume":"40","author":"Y Liu","year":"2020","journal-title":"Bioscience Reports"},{"issue":"3","key":"pone.0307577.ref046","doi-asserted-by":"crossref","first-page":"H1241","DOI":"10.1152\/ajpheart.2001.280.3.H1241","article-title":"Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression","volume":"280","author":"JD Huber","year":"2001","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"1","key":"pone.0307577.ref047","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0006-8993(99)01479-1","article-title":"Peripheral injections of Freund\u2019s adjuvant in mice provoke leakage of serum proteins through the blood\u2013brain barrier without inducing reactive gliosis","volume":"832","author":"AG Rabchevsky","year":"1999","journal-title":"Brain Research"},{"issue":"1","key":"pone.0307577.ref048","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/1742-2094-8-164","article-title":"Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size","volume":"8","author":"\u00c1 D\u00e9nes","year":"2011","journal-title":"Journal of Neuroinflammation"},{"issue":"9","key":"pone.0307577.ref049","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1099\/0022-1317-50-9-812","article-title":"Tumour necrosis factor-\u03b1 causes an increase in blood-brain barrier permeability during sepsis","volume":"50","author":"N TSAO","year":"2001","journal-title":"Journal of Medical Microbiology"},{"issue":"7","key":"pone.0307577.ref050","doi-asserted-by":"crossref","first-page":"ofz257","DOI":"10.1093\/ofid\/ofz257","article-title":"Plasma Proinflammatory Cytokines Are Markers of Disease Severity and Bacterial Burden in Pulmonary Tuberculosis","volume":"6","author":"NP Kumar","year":"2019","journal-title":"Open Forum Infect Dis"},{"issue":"3","key":"pone.0307577.ref051","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.3390\/ijms24032852","article-title":"Blood-Brain Barrier Integrity Damage in Bacterial Meningitis: The Underlying Link, Mechanisms, and Therapeutic Targets","volume":"24","author":"R Yang","year":"2023","journal-title":"International Journal of Molecular Sciences"},{"issue":"3","key":"pone.0307577.ref052","doi-asserted-by":"crossref","first-page":"e0214088","DOI":"10.1371\/journal.pone.0214088","article-title":"Reference set of Mycobacterium tuberculosis clinical strains: A tool for research and product development","volume":"14","author":"S Borrell","year":"2019","journal-title":"PLoS One"},{"issue":"14","key":"pone.0307577.ref053","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1128\/JB.00166-10","article-title":"Variation among Genome Sequences of H37Rv Strains of Mycobacterium tuberculosis from Multiple Laboratories","volume":"192","author":"TR Ioerger","year":"2010","journal-title":"Journal of Bacteriology"},{"issue":"6707","key":"pone.0307577.ref054","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/24206","article-title":"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence","volume":"396","author":"ST Cole","year":"1998","journal-title":"Nature"},{"issue":"1","key":"pone.0307577.ref055","doi-asserted-by":"crossref","first-page":"7068","DOI":"10.1038\/s41467-022-34853-x","article-title":"A comprehensive update to the Mycobacterium tuberculosis H37Rv reference genome","volume":"13","author":"P Chitale","year":"2022","journal-title":"Nature Communications"},{"issue":"11","key":"pone.0307577.ref056","doi-asserted-by":"crossref","first-page":"6740","DOI":"10.4049\/jimmunol.162.11.6740","article-title":"Mycobacterium tuberculosis CDC1551 Induces a More Vigorous Host Response In Vivo and In Vitro, But Is Not More Virulent Than Other Clinical Isolates1","volume":"162","author":"C Manca","year":"1999","journal-title":"The Journal of Immunology"},{"issue":"10","key":"pone.0307577.ref057","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1093\/infdis\/jiz663","article-title":"Mycobacterium tuberculosis HN878 Infection Induces Human-Like B-Cell Follicles in Mice","volume":"221","author":"JA Chore\u00f1o-Parra","year":"2020","journal-title":"J Infect Dis"},{"issue":"4","key":"pone.0307577.ref058","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tube.2010.05.002","article-title":"Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model","volume":"90","author":"R Hernandez Pando","year":"2010","journal-title":"Tuberculosis"},{"issue":"4","key":"pone.0307577.ref059","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.4049\/jimmunol.179.4.2532","article-title":"The Cellular Immune Response to Mycobacterium tuberculosis Infection in the Guinea Pig1","volume":"179","author":"D Ordway","year":"2007","journal-title":"The Journal of Immunology"},{"issue":"5","key":"pone.0307577.ref060","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1165\/rcmb.2008-0154TR","article-title":"What animal models teach humans about tuberculosis","volume":"39","author":"AS Dharmadhikari","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"4","key":"pone.0307577.ref061","first-page":"324","article-title":"The guinea pig as a model of infectious diseases","volume":"58","author":"DJ Padilla-Carlin","year":"2008","journal-title":"Comparative medicine"},{"key":"pone.0307577.ref062","doi-asserted-by":"crossref","first-page":"1090109","DOI":"10.3389\/fnagi.2022.1090109","article-title":"Extensive accumulation of misfolded protein aggregates during natural aging and senescence","volume":"14","author":"K Cuanalo-Contreras","year":"2022","journal-title":"Front Aging Neurosci"},{"issue":"9","key":"pone.0307577.ref063","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1093\/gerona\/glac073","article-title":"Nontransgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer\u2019s Disease","volume":"77","author":"D Wahl","year":"2022","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"pone.0307577.ref064","doi-asserted-by":"crossref","first-page":"571372","DOI":"10.3389\/fphys.2020.571372","article-title":"The Dunkin Hartley Guinea Pig Is a Model of Primary Osteoarthritis That Also Exhibits Early Onset Myofiber Remodeling That Resembles Human Musculoskeletal Aging","volume":"11","author":"RV Musci","year":"2020","journal-title":"Front Physiol"},{"issue":"6","key":"pone.0307577.ref065","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1080\/03008207.2017.1409218","article-title":"Development of a microcomputed tomography scoring system to characterize disease progression in the Hartley guinea pig model of spontaneous osteoarthritis","volume":"59","author":"LB Radakovich","year":"2018","journal-title":"Connect Tissue Res"},{"issue":"2","key":"pone.0307577.ref066","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0301-0082(98)00034-3","article-title":"Inflammation and glial responses in ischemic brain lesions","volume":"56","author":"G Stoll","year":"1998","journal-title":"Progress in Neurobiology"},{"issue":"2","key":"pone.0307577.ref067","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1254\/jphs.09292SC","article-title":"Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells","volume":"112","author":"T Nishioku","year":"2010","journal-title":"J Pharmacol Sci"},{"issue":"2","key":"pone.0307577.ref068","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.neuron.2008.01.003","article-title":"The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders","volume":"57","author":"BV Zlokovic","year":"2008","journal-title":"Neuron"},{"key":"pone.0307577.ref069","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3389\/fncel.2020.00198","article-title":"Overview of General and Discriminating Markers of Differential Microglia Phenotypes","volume":"14","author":"AM Jurga","year":"2020","journal-title":"Front Cell Neurosci"},{"issue":"2","key":"pone.0307577.ref070","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0006-8993(01)02378-2","article-title":"Time course of glial proliferation and glial apoptosis following excitotoxic CNS injury","volume":"902","author":"M Dihn\u00e9","year":"2001","journal-title":"Brain Res"},{"issue":"1","key":"pone.0307577.ref071","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12974-019-1643-9","article-title":"Microglial activation by microbial neuraminidase through TLR2 and TLR4 receptors","volume":"16","author":"Grondona JM Fern\u00e1ndez-Arjona MdM","year":"2019","journal-title":"Journal of Neuroinflammation"},{"issue":"8","key":"pone.0307577.ref072","article-title":"ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease","volume":"9","author":"DSA Simpson","year":"2020","journal-title":"Antioxidants (Basel)"},{"issue":"3","key":"pone.0307577.ref073","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1006\/bbrc.1996.1112","article-title":"A Novel Geneiba1in the Major Histocompatibility Complex Class III Region Encoding an EF Hand Protein Expressed in a Monocytic Lineage","volume":"224","author":"Y Imai","year":"1996","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"7","key":"pone.0307577.ref074","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.3390\/cells10071812","article-title":"The Complement System: A Powerful Modulator and Effector of Astrocyte Function in the Healthy and Diseased Central Nervous System","volume":"10","author":"M Pekna","year":"2021","journal-title":"Cells"},{"issue":"1","key":"pone.0307577.ref075","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s40478-019-0735-1","article-title":"Complement 3(+)-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia","volume":"7","author":"K Hartmann","year":"2019","journal-title":"Acta Neuropathol Commun"},{"issue":"3","key":"pone.0307577.ref076","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"C Escartin","year":"2021","journal-title":"Nature Neuroscience"},{"key":"pone.0307577.ref077","article-title":"Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury","volume":"14","author":"T Yang","year":"2020","journal-title":"Frontiers in Cellular 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Sci"},{"issue":"5","key":"pone.0307577.ref081","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1096\/fj.10-177279","article-title":"Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation","volume":"25","author":"L Li","year":"2011","journal-title":"Faseb j"},{"issue":"1","key":"pone.0307577.ref082","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/WNR.0b013e3282f2b4eb","article-title":"Altered blood\u2013brain barrier integrity in adult aquaporin-4 knockout mice","volume":"19","author":"J Zhou","year":"2008","journal-title":"NeuroReport"},{"issue":"3","key":"pone.0307577.ref083","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.neuroscience.2009.03.069","article-title":"AQP4 gene deletion in mice does not alter blood\u2013brain barrier integrity or brain morphology","volume":"161","author":"S Saadoun","year":"2009","journal-title":"Neuroscience"},{"issue":"10","key":"pone.0307577.ref084","doi-asserted-by":"crossref","DOI":"10.3390\/cells12101418","article-title":"LPS-Induced Systemic Inflammation Affects the Dynamic Interactions of Astrocytes and Microglia with the Vasculature of the Mouse Brain Cortex","volume":"12","author":"E Xingi","year":"2023","journal-title":"Cells"},{"key":"pone.0307577.ref085","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1146\/annurev.cellbio.17.1.463","article-title":"How matrix metalloproteinases regulate cell behavior","volume":"17","author":"MD Sternlicht","year":"2001","journal-title":"Annu Rev Cell Dev Biol"},{"issue":"39","key":"pone.0307577.ref086","doi-asserted-by":"crossref","first-page":"9841","DOI":"10.1523\/JNEUROSCI.1993-06.2006","article-title":"Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury","volume":"26","author":"JY Hsu","year":"2006","journal-title":"J Neurosci"},{"issue":"17","key":"pone.0307577.ref087","doi-asserted-by":"crossref","first-page":"7526","DOI":"10.1523\/JNEUROSCI.22-17-07526.2002","article-title":"Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events","volume":"22","author":"LJ Noble","year":"2002","journal-title":"J Neurosci"},{"key":"pone.0307577.ref088","doi-asserted-by":"crossref","first-page":"914104","DOI":"10.1155\/2013\/914104","article-title":"The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas","volume":"2013","author":"H K\u00f6nnecke","year":"2013","journal-title":"Clin Dev Immunol"},{"issue":"6","key":"pone.0307577.ref089","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.freeradbiomed.2004.06.008","article-title":"Mitochondrial redox control of matrix metalloproteinases","volume":"37","author":"KK Nelson","year":"2004","journal-title":"Free 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by Angiostrongylus cantonensis","volume":"8","author":"P-S Chiu","year":"2013","journal-title":"PLOS ONE"},{"issue":"4","key":"pone.0307577.ref093","doi-asserted-by":"crossref","first-page":"e1000874","DOI":"10.1371\/journal.ppat.1000874","article-title":"Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8","volume":"6","author":"A Schubert-Unkmeir","year":"2010","journal-title":"PLoS Pathog"},{"key":"pone.0307577.ref094","article-title":"The role of the immune system in driving neuroinflammation","volume":"4","author":"NC C","year":"2020","journal-title":"Brain Neurosci Adv"},{"issue":"5","key":"pone.0307577.ref095","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/cne.21668","article-title":"CD11c\/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain","volume":"508","author":"K Bulloch","year":"2008","journal-title":"Journal of Comparative Neurology"},{"issue":"1","key":"pone.0307577.ref096","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1038\/s41467-018-07053-9","article-title":"Tissue-resident memory T cells populate the human brain","volume":"9","author":"J Smolders","year":"2018","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0307577.ref097","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s12974-015-0329-1","article-title":"Functional differences between microglia and monocytes after ischemic stroke","volume":"12","author":"RM Ritzel","year":"2015","journal-title":"Journal of Neuroinflammation"},{"issue":"1","key":"pone.0307577.ref098","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nn.3599","article-title":"Identification of a unique TGF-\u03b2\u2013dependent molecular and functional signature in microglia","volume":"17","author":"O Butovsky","year":"2014","journal-title":"Nature Neuroscience"},{"issue":"124","key":"pone.0307577.ref099","doi-asserted-by":"crossref","DOI":"10.3791\/55781-v","article-title":"Analysis of Microglia and Monocyte-derived Macrophages from the Central Nervous System by Flow Cytometry","author":"E Martin","year":"2017","journal-title":"J Vis Exp"},{"key":"pone.0307577.ref100","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.582825","article-title":"Role of Peripheral Immune Cells-Mediated Inflammation on the Process of Neurodegenerative Diseases","volume":"11","author":"Q Yang","year":"2020","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"pone.0307577.ref101","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12860-018-0172-1","article-title":"Inflammation caused by peripheral immune cells across into injured mouse blood brain barrier can worsen postoperative cognitive dysfunction induced by isoflurane","volume":"19","author":"H Zhu","year":"2018","journal-title":"BMC Cell 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