title: IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation.
abstract: Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ-/-) or IFN-γ receptor knockout (IFN-γR-/-) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-l-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signaling-deficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.
authors: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249.
authors: Rebecca A
authors: RA
authors: Sosa
authors: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249.
authors: Cathi
authors: C
authors: Murphey
authors: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249.
authors: Rachel R
authors: RR
authors: Robinson
authors: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249 Thomas.Forsthuber@utsa.edu.
authors: Thomas G
authors: TG
authors: Forsthuber
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015227:Lipid Peroxidation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor
keywords: APC; EAE; T cell; interferon-gamma; myelin debris