The Interdependent, Overlapping, and Differential Roles of Type I and II IFNs in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

Type I IFNs (IFN-α and IFN-β) and type II IFN (IFN-γ) mediate both regulation and inflammation in multiple sclerosis (MS), neuromyelitis optica (NMO) and in experimental autoimmune encephalomyelitis (EAE). However the underlying mechanism for these Janus-like activities of type I and II IFNs in neuroinflammation remains unclear. Although endogenous type I IFN-signaling provides a protective response in neuroinflammation, we find that when IFN-γ signaling is ablated, type I IFNs drive inflammation resulting in exacerbated EAE. IFN-γ has disease stage-specific opposing function in EAE. Treatment of mice with IFN-γ during initiation phase of EAE leads to enhanced severity of disease. In contrast, IFN-γ treatment during effector phase attenuated disease. This immunosuppressive activity of IFN-γ required functional type I IFN-signaling. In IFN-α/β receptor (IFNAR) deficient mice, IFN-γ treatment during effector phase of EAE exacerbated disease. Using an adoptive transfer-EAE model, we found that T-cell intrinsic type I and type II IFN signals are simultaneously required to establish chronic EAE by encephalitogenic Th1 cells. However in Th17 cells loss of either IFN signals leads to the development of a severe chronic disease. The data implies that type I and type II IFN signals have independent but non-redundant role in restraining encephalitogenic Th17 cells in vivo. Overall our data show that type I and type II IFNs function in an integrated manner to regulate the pathogenesis in EAE.

FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus

“…IFNγ has also been shown to elicit antiinflammatory effects (Muhl and Pfeilschifter, 2003), protect neurons from damage initiated by viral infection (Geiger et al, 1997;Rodriguez et al, 2003), protect cultured hippocampal neurons against glutamate-induced excitotoxic death (Lee et al, 2006) and alleviate status epilepticus-induced neuronal damage in the hippocampus of rats (Ryu et al, 2010). Furthermore, enhancement of both type 1 and 2 interferons limits inflammation and disease progression in models of multiple sclerosis (Lin et al, 2007;Bowen and Olson, 2013;Naves et al, 2013). Thus, increasing interferon expression in combination with a reduction in pro-inflammatory cytokines may limit the neuroinflammatory and possibly neurodegenerative cascades in the hippocampus following TLR3 activation.…”

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions

“…Progressive EAE was induced in the C57BL/6 mice (8–12 weeks) according to a previously described protocol (Axtell et al 2004; Naves et al 2013). Briefly, an immunization mixture of 150 μg myelin oligodendrocyte protein (MOG 38–49 ) (CPC Scientific), 500 μg Mycobacterium tuberculosis and incomplete Freund’s adjuvant was injected subcutaneously in the flank region on day 0 followed by an intraperitoneal (i.p.)…”

IFN‐γ promotes transendothelial migration of CD4+ T cells across the blood–brain barrier

“…IFN‐γ is also known to be produced by Th17 cells, and Th17 cells lacking IFN‐γ 2 or transcription factor T‐bet do not cause EAE 10 . Interestingly, injection of IFN‐γ in EAE mice during the induction phase of EAE promoted earlier onset of the disease, whereas its application during the chronic phase ameliorated the disease 11 . Collectively, these studies suggest that IFN‐γ exerts its effect in a stage‐specific manner and may perform different roles in the secondary lymphoid tissues, at the blood–brain barrier (BBB) and in the CNS parenchyma.…”