Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice.
Activation of transcription factor NF-kappaB in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic. Here we show that CNS-restricted ablation of 'upstream' NF-kappaB activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of multiple sclerosis, suggesting that 'canonical' NF-kappaB activation in cells of the CNS has a mainly pathogenic function in autoimmune demyelinating disease. NF-kappaB inhibition prevented the expression of proinflammatory cytokines, chemokines and the adhesion molecule VCAM-1 from CNS-resident cells. Thus, NF-kappaB-dependent gene expression in non-microglial cells of the CNS provides a permissive proinflammatory milieu that is critical for CNS inflammation and tissue damage in autoimmune demyelinating disease.
van Loo
Geert
G
European Molecular Biology Laboratory Mouse Biology Unit, I-00016 Monterotondo, Italy.
De Lorenzi
Rossana
R
Schmidt
Hauke
H
Huth
Marion
M
Mildner
Alexander
A
Schmidt-Supprian
Marc
M
Lassmann
Hans
H
Prinz
Marco R
MR
Pasparakis
Manolis
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D051550:I-kappa B Kinase