Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS.

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.

• 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
• Journal: Nature neuroscience (Nat Neurosci) Vol. 15 Issue 1 Pg. 98-106 (Dec 04 2011) ISSN: 1546-1726 [Electronic] United States
• PMID: 22138643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Interferon alpha-beta
• RNA Helicases

Topics

• Animals
• Autoimmunity (immunology)
• Cell Differentiation (immunology)
• Cell Survival (immunology)
• Central Nervous System (enzymology, immunology, metabolism)
• Cytosol (enzymology)
• Dendritic Cells (immunology, metabolism)
• Encephalomyelitis, Autoimmune, Experimental (enzymology, immunology, metabolism)
• Mice
• RNA Helicases (metabolism)
• Receptor, Interferon alpha-beta (metabolism)
• T-Lymphocytes (immunology, metabolism)