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

Abstract

Background 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. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. Methods To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelB ΔAST ), oligodendrocytes (RelB ΔOLIGO ), or neural progenitor-derived cells (RelB ΔNP ). 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. Results Despite 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. Conclusions These 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1548-7) contains supplementary material, which is available to authorized users.

A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis

“…Our results are to our knowledge the first to directly investigate the function of RelB in T cells using an active EAE model in otherwise unmanipulated animals. Thus, similarly to what was observed in oligodendrocytes or dendritic cells, RelB appears to exert a pathogenic effect in T cells during CNS autoimmunity 38 , 39 .…”

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

“…Highly expressed RelB in astrocytes may induce immune tolerance in experimental neuroinflammation due to decreased pro-inflammatory cytokines such as IL-1β, IL-6 and IL-8 [203]. Moreover, the severity of EAE with RelB specifically deleted in astrocytes is similar with control mice [201]. Taken together, regulating the expression of RelB in oligodendrocytes and astrocytes may be an option to treat MS in the future.…”

“…MS lesions are featured by oligodendrocyte death and axon degeneration. Gupta et al found that the deficiency of RelB in oligodendrocytes decreased the severity of EAE through promoting survival of mature oligodendrocytes [201]. As the most abundant cell type in the CNS, astrocytes are important regulators of inflammation and essential for maintaining CNS homeostasis [202].…”

NF-κB Activation Accounts for the Cytoprotective Effects of PERK Activation on Oligodendrocytes during EAE

“…We also found that oligodendrocyte-specific expression of Ik BaDN dramatically increases EAE diseases severity; however, we were not able to collect tissues to determine the effects of Ik BaDN expression on oligodendrocytes during EAE because of early, sudden death of these EAE mice (Stone et al, 2017). Moreover, a report showed that oligodendrocyte-specific deletion of RelB attenuates EAE-induced oligodendrocyte death and demyelination and that the beneficial effects of RelB deletion in oligodendrocytes during EAE are associated with p65 NF-k B activation (Gupta et al, 2019). In this study, we generated a mouse model that expresses IKK2ca specifically in oligodendrocytes.…”

“…Because of early, sudden death of these EAE mice, we could not collect CNS tissues to determine the effects of Ik BaDN expression on oligodendrocyte during EAE (Stone et al, 2017). Nevertheless, another study showed that oligodendrocyte-specific deletion of RelB attenuates EAE-induced oligodendrocyte death and demyelination (Gupta et al, 2019). Moreover, a report mentioned that IKK2 deletion in oligodendrocytes, using IKK2 loxP/loxP ; MOG/Cre mice, does not affect EAE development but fell short to show the efficiency and specificity of Cre-mediated recombination of floxed IKK2 alleles in these mice (Raasch et al, 2011).…”