TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
TL;DR: In this paper, the authors focused on the activity of the ENV protein and investigated how it can be neutralized for an improved remyelination in the context of multiple sclerosis.
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 neuroregenerative 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 a MS specific pathogenic entity and its envelope (ENV) protein was previously identified as negative regulator of OPC maturation – hence 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 an improved remyelination. ENV mediated activation of TLR4 increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress and results in myelin-associated deficits including decreased levels of oligodendroglial maturation marker expression and morphological alterations. 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 were 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.
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TL;DR: Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) with a well-documented role in the innate and adaptive immune responses as mentioned in this paper , and their activation has also been linked to several brain functions including neurogenesis and synaptogenesis.
4 citations
TL;DR: In this article , the authors discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states, including traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts.
Abstract: Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and (4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.
3 citations
TL;DR: In this article , the authors discuss the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERVactivating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.
Abstract: Human endogenous retroviruses (ERVs) are ancestorial retroviral elements that were integrated into our genome through germline infections and insertions during evolution. They have repeatedly been implicated in the aetiology and pathophysiology of numerous human disorders, particularly in those that affect the central nervous system. In addition to the known association of ERVs with multiple sclerosis and amyotrophic lateral sclerosis, a growing number of studies links the induction and expression of these retroviral elements with the onset and severity of neurodevelopmental and psychiatric disorders. Although these disorders differ in terms of overall disease pathology and causalities, a certain degree of (subclinical) chronic inflammation can be identified in all of them. Based on these commonalities, we discuss the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERV-activating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.
1 citations
TL;DR: This review collects studies of the interaction between HERV elements and Toll-like receptors and attempts to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases.
Abstract: Human endogenous retroviruses (HERVs) are estimated to comprise ∼8% of the entire human genome, but the vast majority of them remain transcriptionally silent in most normal tissues due to accumulated mutations. However, HERVs can be frequently activated and detected in various tissues under certain conditions. Nucleic acids or proteins produced by HERVs can bind to pattern recognition receptors of immune cells or other cells and initiate an innate immune response, which may be involved in some pathogenesis of diseases, especially cancer and autoimmune diseases. In this review, we collect studies of the interaction between HERV elements and Toll-like receptors and attempt to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases.
1 citations
TL;DR: In this paper , the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice was investigated.
Abstract: Abstract Background The “missing” link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. Methods Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. Results Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L , MusD , and IAP transcription, cGAS–IFI16–STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. Conclusions Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.
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TL;DR: This method is used to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-γ (IFN-γ) signaling and low-molecular-weight inhibitors.
Abstract: Cellular processes can only be understood as the dynamic interplay of molecules. There is a need for techniques to monitor interactions of endogenous proteins directly in individual cells and tissues to reveal the cellular and molecular architecture and its responses to perturbations. Here we report our adaptation of the recently developed proximity ligation method to examine the subcellular localization of protein-protein interactions at single-molecule resolution. Proximity probes-oligonucleotides attached to antibodies against the two target proteins-guided the formation of circular DNA strands when bound in close proximity. The DNA circles in turn served as templates for localized rolling-circle amplification (RCA), allowing individual interacting pairs of protein molecules to be visualized and counted in human cell lines and clinical specimens. We used this method to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-gamma (IFN-gamma) signaling and low-molecular-weight inhibitors.
2,228 citations
TL;DR: The mechanisms of remyelination provide critical clues for regeneration biologists that help them to determine why remYelination fails in MS and in other demyelinating diseases and how it might be enhanced therapeutically.
Abstract: Remyelination involves reinvesting demyelinated axons with new myelin sheaths. In stark contrast to the situation that follows loss of neurons or axonal damage, remyelination in the CNS can be a highly effective regenerative process. It is mediated by a population of precursor cells called oligodendrocyte precursor cells (OPCs), which are widely distributed throughout the adult CNS. However, despite its efficiency in experimental models and in some clinical diseases, remyelination is often inadequate in demyelinating diseases such as multiple sclerosis (MS), the most common demyelinating disease and a cause of neurological disability in young adults. The failure of remyelination has profound consequences for the health of axons, the progressive and irreversible loss of which accounts for the progressive nature of these diseases. The mechanisms of remyelination therefore provide critical clues for regeneration biologists that help them to determine why remyelination fails in MS and in other demyelinating diseases and how it might be enhanced therapeutically.
1,325 citations
TL;DR: Evidence is provided that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.
Abstract: Impaired function/differentiation of progenitor cells might provide an explanation for the limited remyelination observed in the majority of chronic multiple sclerosis lesions. Here, we establish that in the normal adult human CNS, the transcription factors Nkx2.2 and Olig2 are strongly expressed in progenitor cells while mature oligodendrocytes are characterized by low levels of Olig2 or Nkx2.2. In vitro studies confirmed the expression of Olig2 in oligodendroglial progenitor cells and mature oligodendrocytes while astrocytes, microglial cells and neurons were negative for Olig2. In early multiple sclerosis lesions, we found Olig2-positive progenitor cells throughout all lesion stages and in periplaque white matter (PPWM). The number of progenitors in PPWM was significantly increased compared with the white matter from controls. In chronic multiple sclerosis lesions progenitor cells were still present, however, in significantly lower numbers than in early multiple sclerosis lesions. A subpopulation of progenitor cells in early multiple sclerosis lesions and PPWM but not in control cases co-expressed NogoA, a marker of mature oligodendrocytes. The co-expression of these two markers suggested that these cells were maturing oligodendrocytes recently recruited from the progenitor pool. In contrast, in chronic multiple sclerosis lesions maturing progenitors were only rarely present. In summary, we provide evidence that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.
723 citations
TL;DR: It is demonstrated that one potential source of remyelinating oligodendrocytes-immature, cycling cells endogenous to adult white matter-is examined, and that this population responds to demyelination by differentiating into myelination oligodends engaging in repair of the lesion.
564 citations
TL;DR: A microglial population in the zebrafish is exploited to study the digestion of neurons in intact living brains and shows that fusion is mediated by the v0-ATPase a1 subunit, which mediates fusion between phagosomes and lysosomes during phagocytosis, a function that is independent of its proton pump activity.
518 citations