title: 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.affiliation: Department of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dann
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Croxford
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gaupp
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.forename: Markus
authors.initials: M
authors.lastname: Knust
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Cornelius
authors.initials: C
authors.lastname: Maihoefer
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002490:Central Nervous System / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020365:RNA Helicases / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D053633:Receptor, Interferon alpha-beta; D020365:RNA Helicases