Interferon-β (IFNβ) is a first-line therapy for patients with relapsing–remitting multiple sclerosis. This study provides insight into the pathways by which type I IFNs can suppress inflammation in the central nervous system (CNS) and suggests a new mechanism by which these pathways could be targeted therapeutically.
The authors looked at the role of the RNA helicases RIG-I and MDA5 — stimulation of which is known to induce type I IFN production — in the context of experimental autoimmune encephalomyelitis (EAE) in mice. Similarly to human multiple sclerosis, EAE is thought to be mediated by T helper 1 (TH1) and TH17 cells. In mice lacking the RIG-I and MDA5 adaptor protein MAVS (also known as IPS1, VISA and CARDIF) that were immunized with a myelin-associated antigen, the peak clinical EAE disease score was markedly increased compared with that of wild-type mice. This correlated with increased numbers of macrophages and T cells in the CNS and increased demyelination. The encephalitogenic T cell response in Mavs−/− mice was shifted further towards TH1 and TH17 cell responses compared with that of wild-type mice, as shown by the increased expression of cytokines and transcription factors associated with these subsets.
These results indicate that the RNA helicases might have a protective role in EAE, and this was confirmed by the administration of ligands for RIG-I and MDA5 to wild-type mice at the peak of disease. Treated mice had markedly decreased disease severity and greatly increased serum levels of IFNβ. The transcripts of TH1 and TH17 cell-associated factors were decreased in number in the CNS of mice treated with RIG-I and MDA5 ligands.
The authors went on to show that this protective effect requires signalling through the type I IFN receptor (IFNAR). IFNAR-deficient mice, which have previously been shown to have more severe EAE than wild-type mice, had no improvement of clinical disease after treatment with RIG-I or MDA5 ligands. Fluorescently labelled ligands for RIG-I or MDA5 injected into mice with EAE mainly reached the spleen — where they were largely taken up by CD11b+CD11c+ dendritic cells (DCs) — and could not be detected in the CNS. The importance of DCs for protection was confirmed by the conditional deletion of Ifnar in DCs; these mice did not have any improvement of disease severity after the administration of RIG-I or MDA5 ligands.
So what is the effect of IFNAR stimulation on DCs? Lymph node cells taken from mice with EAE after RNA helicase stimulation were exposed to a myelin-associated antigen in vitro; T cell proliferation and IFNγ and interleukin-17 production were markedly decreased compared with the levels in cells taken from non-treated mice, and this was dependent on the presence of IFNAR on DCs.
Overall, the data indicate that the stimulation of RIG-I and MDA5 in peripheral DCs can inhibit encephalitogenic TH1 and TH17 cells through a type I IFN response that engages IFNAR on DCs. Stimulating the endogenous production of type I IFNs in this manner could be used therapeutically to bypass the formation of neutralizing antibodies specific for exogenous IFNβ, an issue that currently limits the clinical efficacy of IFN therapy.
ORIGINAL RESEARCH PAPER
Dann, A. et al. Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS. Nature Neurosci. 4 Dec 2011 (doi:10.1038/nn.2964)
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Minton, K. Interfering with brain inflammation. Nat Rev Immunol 12, 77 (2012). https://doi.org/10.1038/nri3154
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DOI: https://doi.org/10.1038/nri3154