Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis.

Nichole M Miller,Bonnie N Dittel,Jun Wang,Yanping Tan

doi:10.3389/fnins.2015.00287

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by T helper (h)1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB) and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on strong EAE data this view is being reevaluated by some investigators in the field.

Highlights

Multiple sclerosis (MS) is an autoimmune disease driven by CD4 T cells of the T helper (h) 1 and/or Th17 subtype (Lovett-Racke et al, 2011)
Since the failure of IFN-γ as a therapeutic treatment for MS, we have uncovered much about the biology of IFN-γ and its receptor
Given the pleiotropic effects of IFN-γ and the fact that its receptor is expressed by virtually all cell types, in retrospect, it is not surprising that its systemic administration failed to have therapeutic benefit in MS

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disease driven by CD4 T cells of the T helper (h) 1 and/or Th17 subtype (Lovett-Racke et al, 2011). The patients completely recovered from the attacks (Panitch et al, 1987; Panitch, 1994) This result has set back future clinical trails targeting IFN-γ or its pathways even though, as discussed below, strong experimental data in EAE suggests that it functions as a potent anti-inflammatory mediator of CNS inflammation. When EAE was induced by immunization with guinea pig MBP disease onset was similar in +/+ and −/− littermate controls, but while the WT underwent recovery the knockout mice exhibited a high mortality rate (Ferber et al, 1996) (Table 1). As with IFN-γ, GM-CSF is a pleiotropic cytokine that can influence EAE induction by a variety of mechanisms including activation of antigen presenting cells, enhancement of pro-inflammatory cytokine production and promotion of leukocyte adhesion and chemotaxis (Shiomi and Usui, 2015). Rather IFN-γ promotes iTreg conversion by inducing Foxp expression generating iTreg with the capacity to suppress the severity of EAE (Wang et al, 2006)

A Role for Neutrophils in MS?

Findings

Concluding Remarks