TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits

Abstract

Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.

Endogenous Retroviruses as Modulators of Innate Immunity

“…Ultimately, this Env–TLR4–CD14 interaction stimulates the production of multiple pro-inflammatory cytokines, such as TNF-a, IL1β, IL-12p40, IL-12p70, and IL6 and pro-inflammatory cell surface proteins (CD80, CD86, CD40, and HLA-DR) in human myeloid cell lineages and promotes the development of a Th1 type immune response [ 77 ]. Following this discovery, MSRV-derived Env and other HERV-W Env proteins have been shown to interact with TLR4 to induce a pro-inflammatory response in a variety of cell-types and situations, including a potential role in the development of type I diabetes (T1D) [ 98 , 99 , 100 , 101 , 102 ].…”

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress

“…Second, the role of other intracellular ERVs transcriptional products sensors including coding or non-coding RNAs, DNAs, and proteins, such as a verity of endosomal TLRs, should be comprehensively identified in chronic stress-induced microglial immuno-inflammation and negative emotional behaviors. For instance, human ERVs-W Env proteins can stimulate both TLR2 and TLR4 and then induce NF-κB activation and pro-inflammatory cytokine secretion [ 59 , 60 ]. TLR3 can detect dsRNA from certain human immunodeficiency virus (HIV) strains and even participate their transactivation, replication, and inflammation [ 61 – 63 ].…”

From Immunity to Neurogenesis: Toll-like Receptors as Versatile Regulators in the Nervous System

“…The proliferation of oligodendrocyte progenitor cells (OPCs) can also be altered by the activation of TLRs. Blocking the interaction of human endogenous retrovirus type W with TLR4 rescued the maturation of OPCs into mature myelinating oligodendrocytes and decreased the secretion of proinflammatory factors (iNOS and IL-6) [ 30 ]. A similar effect was observed on traumatic brain injury (TBI), in which the postinjury release of HMGB1 caused a decrease in OPC proliferation through TLR2/TLR4, revealing the participation of these receptors in the regulation of OPCs [ 31 ].…”