Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells.
Relapses and disease exacerbations are vexing features of multiple sclerosis. Osteopontin (Opn), which is expressed in multiple sclerosis lesions, is increased in patients' plasma during relapses. Here, in models of multiple sclerosis including relapsing, progressive and multifocal experimental autoimmune encephalomyelitis (EAE), Opn triggered recurrent relapses, promoted worsening paralysis and induced neurological deficits, including optic neuritis. Increased inflammation followed Opn administration, whereas its absence resulted in more cell death of brain-infiltrating lymphocytes. Opn promoted the survival of activated T cells by inhibiting the transcription factor Foxo3a, by activating the transcription factor NF-kappaB through induction of phosphorylation of the kinase IKKbeta and by altering expression of the proapoptotic proteins Bim, Bak and Bax. Those mechanisms collectively suppressed the death of myelin-reactive T cells, linking Opn to the relapses and insidious progression characterizing multiple sclerosis.
Hur
Eun Mi
EM
Interdepartmental Program in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Youssef
Sawsan
S
Haws
M Edward
ME
Zhang
Susan Y
SY
Sobel
Raymond A
RA
Steinman
Lawrence
L
D000818:Animals; D002470:Cell Survival / Q000276:immunology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053495:Osteopontin / Q000494:pharmacology / Q000502:physiology*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D053495:Osteopontin