Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE

The mediators that drive the progressive phase of multiple sclerosis remain undefined. Weiner and colleagues find that 15α-hydroxycholestene is expressed abundantly only during progressive multiple sclerosis and activates macrophages, microglia and astrocytes via poly(ADP-ribose) polymerase 1. Multi...

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Bibliographic Details
Published in:Nature immunology Vol. 10; no. 9; pp. 958 - 964
Main Authors: Farez, Mauricio F, Quintana, Francisco J, Gandhi, Roopali, Izquierdo, Guillermo, Lucas, Miguel, Weiner, Howard L
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.09.2009
Nature Publishing Group
Subjects:
Adult
Aged
Analysis
Animals
Autoimmune diseases
Biomedical and Life Sciences
Biomedicine
Care and treatment
Central nervous system
Diagnosis
Encephalomyelitis, Autoimmune, Experimental - immunology
Female
Humans
Hydroxycholesterols - blood
Immunology
Infectious Diseases
Male
Mice
Mice, Inbred NOD
Middle Aged
Multiple sclerosis
Multiple Sclerosis, Chronic Progressive - immunology
Physiology, Pathological
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - physiology
Risk factors
Toll-Like Receptor 2 - immunology
Toll-Like Receptor 2 - physiology
ISSN:1529-2908, 1529-2916, 1529-2916
Online Access:Get full text
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Summary:The mediators that drive the progressive phase of multiple sclerosis remain undefined. Weiner and colleagues find that 15α-hydroxycholestene is expressed abundantly only during progressive multiple sclerosis and activates macrophages, microglia and astrocytes via poly(ADP-ribose) polymerase 1. Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15α-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2–PARP-1 pathway is a potential new therapeutic target in SPMS.
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These authors contributed equally to this work.
ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/ni.1775