title: Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain.
abstract: OBJECTIVE
  Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model.
  
  
  METHODS
  NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected.
  
  
  RESULTS
  We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions.
  
  
  CONCLUSIONS
  Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.
authors.affiliation: Academic Neurosurgery Unit, St. George's, University of London, London, UK.
authors.forename: Samira
authors.initials: S
authors.lastname: Saadoun
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.forename: Claire
authors.initials: C
authors.lastname: MacDonald
authors.forename: B Anthony
authors.initials: BA
authors.lastname: Bell
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007074:Immunoglobulin G; D011480:Protease Inhibitors