Cytosolic RIG-I-like Helicases Act As Negative Regulators of Sterile Inflammation in the CNS

Overview

Journal Nat Neurosci

Date 2011 Dec 6

PMID 22138643

Citations 38

Authors

Angela Dann

Hendrik Poeck

Andrew L Croxford

Stefanie Gaupp

Katrin Kierdorf

Markus Knust

Dietmar Pfeifer

Cornelius Maihoefer

Stefan Endres

Ulrich Kalinke

Sven G Meuth

Heinz Wiendl

Klaus-Peter Knobeloch

Shizuo Akira

Ari Waisman

Gunther Hartmann

Marco Prinz

Affiliations

Soon will be listed here.

Abstract

The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.

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