Innate Interferons Regulate CNS Inflammation

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently, there is no cure for MS, however a standard first-line therapy is recombinant interferon (IFN)-beta. IFN-beta belongs to the family of type I IFNs, which also include IFN-alpha. These engage to one common receptor, IFNAR. Type I IFNs can be induced by several innate immune receptors, including toll-like receptors (TLRs), through signalling cascades involving either interferon regulatory factors (IRFs) or nuclear factor-kappa B (NF-kB). Several studies have identified a protective effect of type I IFNs in relation to experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Mice that lack IFN-beta or have disrupted IFNAR-signaling develop more severe disease, whereas peripheral IFN-beta treatment reduced disease severity and delayed onset. Furthermore, it was recently shown that induction of type I IFNs in the CNS of mice by a TLR3-ligand was protective against EAE. We are now investigating another potential IFN-inducing receptor that signals through NF-kB. Receptor activator of NF-kB (RANK) belongs to the TNF-receptor superfamily and has been shown to induce IFN-beta in medullary thymic epithelial cells affecting autoimmune regulatory processes and osteoclast precursor cells in association to bone mass homeostasis. Whether RANK-signaling is capable of inducing type I IFNs within the CNS has not yet been studied. Preliminary data from IFN-beta-luciferase reporter mice already show that RANK-signaling by intrathecally applied RANKL can induce CNS-endogenous IFN-beta. Experiments in IFN-beta-yellow fluorescence protein reporter mice identify extraparenchymal cells as one source of this IFN-beta and these will be identified using immunostaining and bone marrow chimera approaches. Studies are underway to examine whether IFN-alpha is also induced and the effect of RANK-induced IFN on EAE. The findings from this study will increase understanding of normal CNS homeostasis as well as identify new targets for MS therapy.