Abstract
Interferon-β (IFN-β) is widely used to treat multiple sclerosis (MS), and its efficacy was demonstrated in the setting of experimental autoimmune encephalomyelitis (EAE), an animal model of MS; however, IFN-β is not effective in treating all cases of MS. Here, we demonstrate that signaling by IFNAR (the shared receptor for IFN-α and IFN-β) on macrophages inhibits activation of Rac1 and the generation of reactive oxygen species (ROS) through suppressor of cytokine signaling 1 (SOCS1). The inhibition of Rac1 activation and ROS generation suppressed the activity of the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome, which resulted in attenuated EAE pathogenicity. We further found that two subsets of EAE could be defined on the basis of their dependency on the NLRP3 inflammasome and that IFN-β was not an effective therapy when EAE was induced in an NLRP3 inflammasome-independent fashion. Thus, our study demonstrates a previously uncharacterized signaling pathway that is involved in the suppression of EAE by IFN-β and characterizes NLRP3-independent EAE, which cannot be treated with IFN-β.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins
-
CARD Signaling Adaptor Proteins
-
CD4-Positive T-Lymphocytes / transplantation
-
Carrier Proteins / genetics
-
Carrier Proteins / physiology*
-
Caspase 1 / physiology
-
Cytoskeletal Proteins / deficiency
-
Disease Models, Animal
-
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / physiopathology
-
Enzyme Activation
-
Gene Expression Regulation / drug effects
-
Inflammasomes / physiology*
-
Interferon beta-1b
-
Interferon-beta / therapeutic use*
-
Interleukin-1beta / biosynthesis
-
Interleukin-1beta / genetics
-
Macrophages / physiology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Neuropeptides / antagonists & inhibitors
-
Neuropeptides / physiology
-
Proto-Oncogene Proteins c-vav / antagonists & inhibitors
-
Proto-Oncogene Proteins c-vav / physiology
-
Reactive Oxygen Species / metabolism
-
Receptor, Interferon alpha-beta / deficiency
-
Receptor, Interferon alpha-beta / physiology*
-
Recombinant Proteins / therapeutic use
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins / antagonists & inhibitors
-
Suppressor of Cytokine Signaling Proteins / physiology
-
rac GTP-Binding Proteins / antagonists & inhibitors
-
rac GTP-Binding Proteins / physiology
-
rac1 GTP-Binding Protein
Substances
-
Apoptosis Regulatory Proteins
-
CARD Signaling Adaptor Proteins
-
Carrier Proteins
-
Cytoskeletal Proteins
-
Ifnar1 protein, mouse
-
Inflammasomes
-
Interleukin-1beta
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Neuropeptides
-
Nlrp3 protein, mouse
-
Proto-Oncogene Proteins c-vav
-
Pycard protein, mouse
-
Rac1 protein, mouse
-
Reactive Oxygen Species
-
Recombinant Proteins
-
Socs1 protein, mouse
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins
-
Vav1 protein, mouse
-
Interferon beta-1b
-
Receptor, Interferon alpha-beta
-
Interferon-beta
-
Caspase 1
-
rac GTP-Binding Proteins
-
rac1 GTP-Binding Protein