The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity.
Uric acid (UA), a product of purine metabolism, is a known scavenger of peroxynitrite (ONOO(-)), which has been implicated in the pathogenesis of multiple sclerosis and experimental allergic encephalomyelitis (EAE). To determine whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO(-) or some other immunoregulatory phenomenon, the effects of UA on Ag presentation, T cell reactivity, Ab production, and evidence of CNS inflammation were assessed. The inclusion of physiological levels of UA in culture effectively inhibited ONOO(-)-mediated oxidation as well as tyrosine nitration, which has been associated with damage in EAE and multiple sclerosis, but had no inhibitory effect on the T cell-proliferative response to myelin basic protein (MBP) or on APC function. In addition, UA treatment was found to have no notable effect on the development of the immune response to MBP in vivo, as measured by the production of MBP-specific Ab and the induction of MBP-specific T cells. The appearance of cells expressing mRNA for inducible NO synthase in the circulation of MBP-immunized mice was also unaffected by UA treatment. However, in UA-treated animals, the blood-CNS barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tissue. These findings are consistent with the notion that UA is therapeutic in EAE by inactivating ONOO(-), or a related molecule, which is produced by activated monocytes and contributes to both enhanced blood-CNS barrier permeability as well as CNS tissue pathology.
Kean
R B
RB
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Spitsin
S V
SV
Mikheeva
T
T
Scott
G S
GS
Hooper
D C
DC
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D009566:Nitrates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D014527:Uric Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
D016166:Free Radical Scavengers; D004676:Myelin Basic Protein; D009566:Nitrates; C039642:peroxynitric acid; D014527:Uric Acid