title: Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats.
abstract: BACKGROUND
  Neuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves. These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells. Typically, these lesions form in a setting of CNS inflammation, where the blood-brain barrier is open for the entry of antibodies and complement. However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions. To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry.
  
  
  RESULTS
  All injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract. Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules. Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested. Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location.
  
  
  CONCLUSIONS
  Our data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site.
authors.affiliation: Department of Neuroimmunology, Medical University Vienna, Center for Brain Research, Spitalgasse 4, Vienna, A-1090, Austria. monika.bradl@meduniwien.ac.at.
authors.forename: Maja
authors.initials: M
authors.lastname: Kitic
authors.forename: Sonja
authors.initials: S
authors.lastname: Hochmeister
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimmer
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Misu
authors.forename: Simone
authors.initials: S
authors.lastname: Mader
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fujihara
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Monika
authors.initials: M
authors.lastname: Bradl
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology; D009471:Neuromyelitis Optica / Q000473:pathology / Q000503:physiopathology*; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D054426:Chemokine CXCL2; C508585:IL1B protein, human; C000594089:IL1B protein, rat; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma