title: Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS.
abstract: Factors that regulate leukocyte entry and spread through CNS parenchyma during different types of CNS insults are incompletely understood. Reactive astrocytes have been implicated in restricting the spread of leukocytes from damaged into healthy parenchyma during the acute and local innate inflammatory events that follow CNS trauma, but the roles of reactive astrocytes during the chronic and widespread CNS inflammation associated with adaptive or acquired immune responses are uncertain. Here, we investigated the effects of transgenically targeted ablation of proliferating, scar-forming reactive astrocytes on the acquired immune inflammation associated with experimental autoimmune encephalitis (EAE). In wild-type mice with EAE, we found that reactive astrocytes densely surrounded perivascular clusters of leukocytes in a manner reminiscent of astrocyte scar formation after CNS trauma. Transgenically targeted ablation of proliferating astrocytes disrupted formation of these perivascular scars and was associated with a pronounced and significant increase in leukocyte entry into CNS parenchyma, including immunohistochemically identified macrophages, T lymphocytes and neutrophils. This exacerbated inflammation was associated with a substantially more severe and rapidly fulminant clinical course. These findings provide experimental evidence that reactive astrocytes form scar-like perivascular barriers that restrict the influx of leukocytes into CNS parenchyma and protect CNS function during peripherally initiated, acquired immune inflammatory responses in the CNS. The findings suggest that loss or disruption of astrocyte functions may underlie or exacerbate the inflammation and pathologies associated with autoimmune diseases of the CNS, including multiple sclerosis.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1763, USA.
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
authors.forename: R Scott
authors.initials: RS
authors.lastname: Peterson
authors.forename: Bingbing
authors.initials: B
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Ao
authors.forename: Laurie Beth J
authors.initials: LB
authors.lastname: Morales
authors.forename: Seema
authors.initials: S
authors.lastname: Tiwari-Woodruff
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology*; D001369:Axons / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002921:Cicatrix / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007958:Leukocyte Count / Q000379:methods; D007962:Leukocytes / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D016900:Neurofilament Proteins / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D017252:CD3 Complex; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D013937:Thymidine Kinase; D017493:Leukocyte Common Antigens