cells Review RelB and Neuroinflammation Karli Mockenhaupt, Alexandra Gonsiewski and Tomasz Kordula * Department of Biochemistry and Molecular Biology, School of Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VI 23298, USA; [email protected] (K.M.); [email protected] (A.G.) * Correspondence: [email protected]; Tel.: +1-(804)-828-0771 Abstract: Neuroinflammation within the central nervous system involves multiple cell types that coordinate their responses by secreting and responding to a plethora of inflammatory mediators. These factors activate multiple signaling cascades to orchestrate initial inflammatory response and subsequent resolution. Activation of NF-κB pathways in several cell types is critical during neu- roinflammation. In contrast to the well-studied role of p65 NF-κB during neuroinflammation, the mechanisms of RelB activation in specific cell types and its roles during neuroinflammatory response are less understood. In this review, we summarize the mechanisms of RelB activation in specific cell types of the CNS and the specialized effects this transcription factor exerts during neuroinflammation. Keywords: neuroinflammation; NF-κB; RelB; astrocytes; microglia; oligodendrocytes; glioblas- toma multiforme 1. Introduction Neuroinflammation is the homeostatic defense mechanism that is activated in the Citation: Mockenhaupt, K.; central nervous system (CNS) and aims at preventing exacerbated damage when faced Gonsiewski, A.; Kordula, T. RelB and with insults such as injury, infection, autoimmune response, or metabolic stress [1–3]. The Neuroinflammation. Cells 2021, 10, innate and adaptive immune systems are activated in response to these insults [4–6]. The 1609. https://doi.org/10.3390/ innate immune system is quicker to react but is nonspecific and is composed of innate cells10071609 immune cells, including the resident microglia of the brain and bone-marrow-derived Academic Editor: Lars monocytes/macrophages [6]. The adaptive immune system, which depends on activation Ove Brandenburg of B cells and T cells, is much more specific but requires time to ramp up [4]. Nevertheless, the CNS is separated from the rest of the body by a blood–brain barrier (BBB) that includes Received: 31 May 2021 both endothelial cells and astrocytes, limiting the entry to the CNS [7]. Therefore, T cell Accepted: 23 June 2021 entry is tightly restricted, especially at the onset of neuroinflammation [7]. In addition Published: 27 June 2021 to the immune cells, other cells, such as astrocytes and oligodendrocytes, modulate the immune response within the CNS [8–11]. Unresolved chronic neuroinflammation can Publisher’s Note: MDPI stays neutral lead to neurodegeneration, which manifests by a gradual obliteration of neuronal cells. with regard to jurisdictional claims in Neurodegeneration embodies the pathologies of several debilitating diseases, including published maps and institutional affil- multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, iations. and amyotrophic lateral sclerosis, among others [12–14]. Neurodegeneration compiles both molecular and cellular events that include an accumulation of protein aggregates, modified mitochondria functions, oxidative responses, and cell death [1,15–19]. Although multiple transcription factors regulate neuroinflammatory responses (reviewed in [20,21]), Copyright: © 2021 by the authors. this review is concentrated on RelB, which is a member of the nuclear factor kappa B Licensee MDPI, Basel, Switzerland. (NF-κB) family of transcription factors. This article is an open access article distributed under the terms and 2. The NF-κB Signaling Pathways conditions of the Creative Commons The NF-κB family of transcription factors includes p65 (RelA), c-Rel, p105/p50 (NF- Attribution (CC BY) license (https:// κB1), p100/p52 (NF-κB2), and RelB, which can be activated by different ligands via distinc- creativecommons.org/licenses/by/ tive signaling pathways that have been extensively studied over the last several decades 4.0/). Cells 2021, 10, 1609. https://doi.org/10.3390/cells10071609 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 19 2. The NF-κB Signaling Pathways Cells 2021, 10, 1609 2 of 18 The NF-κB family of transcription factors includes p65 (RelA), c-Rel, p105/p50 (NF- κB1), p100/p52 (NF-κB2), and RelB, which can be activated by different ligands via dis- tinctive signaling pathways that have been extensively studied over the last several dec- (reviewedades (reviewed in [22 –in24 [22]). The–24]). canonical The canonical NF-κB NF pathway-κB pathway is triggered is triggered by an array by an of array inflamma- of in- toryflamma stimuli,tory stimuli, including including proinflammatory proinflammatory cytokines cytokines (i.e., tumor (i.e. necrosis, tumor necrosis factor α (TNFfactorα α) and(TNFα) interleukin-1 and interleukinβ (IL-1-β1β)), (IL molecules-1β)), molecules recognized recognized by the pattern-recognitionby the pattern-recognition receptors re- (i.e.,ceptors Toll-like (i.e., Toll receptor-like receptor (TLRs) ligands),(TLRs) ligands), and antigens, and antigens, among among others others [23–26 [23]) (Figure–26]) (F1ig-). Theure 1). engagement The engagement of the canonicalof the canonical pathway pathway rapidly rapidly activates activates the inhibitor the inhibitor of κB of kinase κB ki- (IKK)nase (IKK) complex, complex, which which is made is made up of threeup of subunits:three subunits: IKKα (alsoIKKα known (also known as IKK1), as IKK1), IKKβ (IKK2),IKKβ (IKK2), and IKK andγ (alsoIKKγ known (also known as NF- asκB NF essential-κB essential modulator modulator (NEMO)) (NEMO)) [27]. Activated[27]. Acti- IKKvatedβ subsequently IKKβ subsequently phosphorylates phosphorylates the inhibitor the inhibitor of NF- ofκB NF (Iκ-B)κB proteins, (IκB) proteins, including including IκBα, whichIκBα, arewhich subsequently are subsequently ubiquitinated ubiquitinated and degraded and degraded by the proteasome by the proteasome [28]. This [28]. releases This thereleases p65/p50 the p65/p50 and c-Rel/p50 and c-Rel/p50 complexes complexes that enter that enter the nucleus the nucleus and induceand induce transcription transcrip- oftion hundreds of hundreds of target of target genes, genes, including including those those encoding encoding major major proinflammatory proinflammatory cytokines cyto- andkines chemokines and chemokines as well as as well IκB αas andIκBα RelB and [22RelB,29 ].[22,29]. While While inflammatory inflammatory cytokines cytokines and chemokinesand chemokines recruit recruit immune immune cells at cells the localat the sites local of sites inflammation, of inflammation, IκBα and IκBα RelB and provide RelB aprovide negative a negative feedback feedback loop needed loop to needed limit the to initiallimit the activation. initial activation. FigureFigure 1.1. ActivationActivation of of RelB RelB by by the the nuclear nuclear factor factor kappa kappa B (NF B- (NF-κB) signalingκB) signaling pathways. pathways. The canon- The ical NF-κB pathway is activated by interleukin 1β (IL-1 β), tumor necrosis factor α (TNFα), and canonical NF-κB pathway is activated by interleukin 1β (IL-1 β), tumor necrosis factor α (TNFα), liposaccharide (LPS). The noncanonical NF-κB pathway is activated by lymphotoxin βLTβ), B and liposaccharide (LPS). The noncanonical NF-κB pathway is activated by lymphotoxin β (LTβ), B cell activating factor of the TNF family (BAFF), and CD40 ligand (CD40L). The canonical activa- celltion activating of RelB/p50 factor occurs of the in cells TNF expressing family (BAFF), high and levels CD40 of RelB ligand (basally (CD40L). or after The induction). canonical activation IκB, in- ofhibitor RelB/p50 of NF occurs-κB; IKK, in cells IκB expressingkinase; NIK, high NF- levelsκB-inducing of RelB kinase; (basally P, or phosphate; after induction). and TRAF3, IκB, inhibitor TNF ofreceptor NF-κB;-a IKK,ssociated IκBkinase; factor 3. NIK, NF-κB-inducing kinase; P, phosphate; and TRAF3, TNF receptor- associated factor 3. The noncanonical pathway (reviewed by [30]) is induced by a much more limited set of liganTheds noncanonical that bind to pathway their receptors, (reviewed which by [ 30include]) is induced B cell activation by a much factor more receptor limited set(BAFFR), of ligands lymphotoxin that bind toβ receptor their receptors, (LTβR), which cluster include of differentiation B cell activation 40 (CD40), factor receptorreceptor β β (BAFFR),activator lymphotoxinof NF-κB (RANK),receptor and fibroblast (LT R), clustergrowth of factor differentiation-inducible 4014 (CD40),(Fn14) [26,31 receptor–34]. κ activatorIn cells ofexpressing NF- B (RANK), NF-κB- andinducing fibroblast kinase growth (NIK), factor-inducible the TNF receptor 14 (Fn14)-associated [26,31–34 factor]. In cells expressing NF-κB-inducing kinase (NIK), the TNF receptor-associated factor (TRAF) 3 (TRAF) 3 forms a complex with TRAF2, the cellular inhibitor of apoptosis (cIAP) 1, cIAP2, forms a complex with TRAF2, the cellular inhibitor of apoptosis (cIAP) 1, cIAP2, and NIK, and NIK, and this leads to constitutive ubiquitination and degradation of NIK [35]. When and this leads to constitutive ubiquitination and degradation of NIK [35]. When the ligands of the noncanonical pathway bind, they induce the recruitment of TRAF3 to their receptors and its subsequent degradation [36]. Simultaneously, the released cIAP1/cIAP2/TRAF2 complex no longer can interact with NIK leading to its accumulation. Accrued NIK phos- Cells 2021,