T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS.
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)(G93A) transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1(G93A) spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRbeta deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1(G93A) (TCRbeta-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.
Chiu
Isaac M
IM
Department of Pathology, Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA. chiu@fas.harvard.edu
Chen
Adam
A
Zheng
Yi
Y
Kosaras
Bela
B
Tsiftsoglou
Stefanos A
SA
Vartanian
Timothy K
TK
Brown
Robert H
RH
Carroll
Michael C
MC
D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D002469:Cell Separation; D019610:Cytoprotection / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000172:deficiency; D000072105:Superoxide Dismutase-1; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D039521:CD11c Antigen; D050505:Mutant Proteins; C000606290:SOD1 protein, human; D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1