Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis.
Metallothionein-I+II (MT-I+II) are antioxidant, neuroprotective proteins, and in this report we have examined their roles during experimental autoimmune encephalomyelitis (EAE) by comparing MT-I+II-knock-out (MTKO) and wild-type mice. We herewith show that EAE susceptibility is higher in MTKO mice relatively to wild-type mice, and that the inflammatory responses elicited by EAE in the central nervous system (CNS) are significantly altered by MT-I+II deficiency. Thus, during EAE the MTKO mice showed increased macrophage and T-lymphocytes infiltration in the CNS, while their reactive astrogliosis was significantly decreased. In addition, the expression of the proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha elicited by EAE was further increased in the MTKO mice, and oxidative stress and apoptosis were also significantly increased in MTKO mice compared to normal mice. The present results strongly suggest that MT-I+II are major factors involved in the inflammatory response of the CNS during EAE and that they play a neuroprotective role in this scenario.
Penkowa
M
M
Department of Medical Anatomy, The Panum Institute, University of Copenhagen, DK-2200, Copenhagen, Denmark.
Espejo
C
C
Martínez-Cáceres
E M
EM
Poulsen
C B
CB
Montalban
X
X
Hidalgo
J
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005911:Gliosis / Q000276:immunology / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008315:Malondialdehyde / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D009410:Nerve Degeneration / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D008668:Metallothionein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse