A detrimental role of RelB in mature oligodendrocytes during experimental acute encephalomyelitis

Angela S Gupta,Ulrich Siebenlist,Tomasz Kordula,Michael Marone,Karli Mockenhaupt,La Shardai N Brown,Debolina D Biswas,Andrew Hoskins

doi:10.1186/s12974-019-1548-7

Abstract

BackgroundMultiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown.MethodsTo examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelBΔAST), oligodendrocytes (RelBΔOLIGO), or neural progenitor-derived cells (RelBΔNP). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level.ResultsDespite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB.ConclusionsThese findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future.

Highlights

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS)
Since Transcription factor RelB (RelB) is upregulated in astrocytes during both EAE [33] and experimental LPS-induced neuroinflammation [24] and limits astrocytic cytokine production [24], we predicted that it may play important functions in non-immune CNS cells during EAE, and its deletion may exaggerate severity of the disease
We crossed nestin-Cre mice with RelBloxp/loxp mice to generate nervous system-restricted RelB conditional knockout mice deficient of RelB in astrocytes, oligodendrocytes, neurons, and adult neural progenitors (Fig. 1a). These mice were born with expected Mendelian ratios (50% WT (RelBloxp/loxp) and 50% RelBΔNP, were phenotypically normal, and displayed no obvious inflammation or neurological deficits

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system (CNS) that manifests with symptoms such as muscle weakness, impaired motor skills and coordination, and sensory loss. The primary cause of the disease is not known, demyelination, primarily mediated by T cells that are reactive to myelin antigens, Ubiquitously expressed transcription factors of the nuclear factor kappa B (NF-κB) family regulate many cellular processes, including cell proliferation and survival, production of inflammatory mediators, differentiation of T cells, and maturation of dendritic cells [3, 4]. Preventing degradation of IκBα decreases the incidence and severity of EAE by decreasing antigenspecific T cell responses [9]. c-Rel, which is a target of the canonical NF-κB pathway, is crucial for the development of EAE, and c-Rel knockout mice are completely protected from the disease. c-Rel knockout mice are characterized by decreased numbers of Th17 and Th1 autoreactive T cells [10]

Methods

Results

Discussion

Conclusion