Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Abstract

The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells.

Macrophages and the Recovery from Acute and Chronic Inflammation

“…In psoriasis, a Th17 disease, serum IFN-γ levels are elevated and correlate with disease severity (20). In multiple sclerosis (MS), another Th17 disease, the role of classically activated macrophages and IFN-γ production appears to be somewhat more complex and can vary depending on the disease phase (21). Early studies identified IFN-γ-producing Th17 cells in lesions (22), and in progressive MS, patients typically have higher serum levels of IFN-γ and TNF (23).…”

“…Early studies identified IFN-γ-producing Th17 cells in lesions (22), and in progressive MS, patients typically have higher serum levels of IFN-γ and TNF (23). However, in the murine model of MS, called experimental autoimmune encephalomyelitis (EAE), mice lacking IFN-γ are more susceptible to severe EAE, and the administration of antibodies to IFN-γ actually exacerbates disease (21). One explanation for this is that IFN-γ production by astrocytes rather than microglia may preserve neuronal integrity (24), but the other obvious explanation is that IFN-γ may be protective by virtue of its well-described inhibition of (pathological) Th17 responses.…”

Chemical and genetic control of IFN γ‐induced MHCII expression

“…Both of these drugs display immunomodulatory activity, with their mechanism of action not fully understood [64,65]. DMF has been approved by the FDA for the treatment of psoriasis and multiple sclerosis (MS) [66][67][68], both autoimmune diseases that have been linked to IFNc expression and activation of CD4 + T cells [26,69,70], implying a possible role for IFNc-induced MHCII expression in disease pathology. To test whether DMF, like Keap1 inhibition, reduces IFNc-induced MHC class II expression, we exposed various cell lines to IFNc in the absence or presence of DMF.…”

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

“…IFN‐γ‐producing Th1 cells enter the CNS and perpetrate the establishment of an inflammatory microenvironment, further facilitating the recruitment of other effector cells, including Th17 cells 2 . IFN‐γ shows inflammatory and regulatory role in a stage‐specific manner in multiple sclerosis (MS) and EAE 3 . Increased IFN‐γ levels have been observed in demyelinating lesions of the CNS during EAE and MS, indicating that it has a pathological role in neuronal autoimmunity 3 .…”

“…IFN‐γ shows inflammatory and regulatory role in a stage‐specific manner in multiple sclerosis (MS) and EAE 3 . Increased IFN‐γ levels have been observed in demyelinating lesions of the CNS during EAE and MS, indicating that it has a pathological role in neuronal autoimmunity 3 . In contrast, it has been also reported that IFN‐γ −/− , IFN‐γ receptor −/− or STAT‐1 −/− mice show increased susceptibility to EAE, suggesting a protective function of IFN‐γ in neuronal autoimmunity 4 , 5 , 6 .…”