Differential effects of integrase strand transfer inhibitors, elvitegravir and raltegravir, on oligodendrocyte maturation: A role for the integrated stress response

Roth, Lindsay M; Zidane, Bassam; Festa, Lindsay; Putatunda, Raj; Romer, Micah; Monnerie, Hubert; Jordan‐Sciutto, Kelly L.; Grinspan, Judith B.

doi:10.1002/glia.23902

Cited by 16 publications

(25 citation statements)

References 43 publications

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“…All experiments were performed in accordance with the guidelines set forth by The Children's Hospital of Philadelphia and The University of Pennsylvania Institutional Animal Care and Use Committees. OPCs were isolated from brains of Postnatal Day 1 Sprague Dawley rats (Charles River Laboratories, Wilmington, MA, RRID: RGD_737891) and plated on T75 flasks as previously described (Jensen et al, 2015; Roth et al, 2020). The OPCs were purified using the “shake‐off” method (McCarthy & de Vellis, 1980).…”

Section: Methodsmentioning

confidence: 99%

“…These results suggest that targeting these pathways might contribute to the alleviation of white matter pathology in HAND, while also linking glutamate signaling to ISR activation, a previously unknown mechanism with broad implications in neuroinflammatory disease with OL dysfunction such as multiple sclerosis (MS). and plated on T75 flasks as previously described (Jensen et al, 2015;Roth et al, 2020). The OPCs were purified using the "shake-off" method (McCarthy & de Vellis, 1980).…”

Section: Oligodendrocyte Precursor Cells (Opcs) Differentiate Into Ma...mentioning

confidence: 99%

“…We examined the effect of HIV-infected cell products on OPC survival and maturation using our well-established primary rat OPC culture model (See et al, 2004). We utilized a previously developed in vitro model of HIV-associated neurotoxicity, which allows the examination of cellular responses to HIV-infected human monocyte-derived macrophage supernatants (HIV/MDMs; Chen et al, 2002;O'Donnell et al, 2006 and plated on T75 flasks as previously described (Jensen et al, 2015;Roth et al, 2020). The OPCs were purified using the "shake-off" method (McCarthy & de Vellis, 1980).…”

Section: Introductionmentioning

confidence: 99%

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HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

Roth

Akay

Grinspan

et al. 2021

Glia

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Despite combined antiretroviral therapy (cART), HIV‐associated neurocognitive disorder (HAND) affects 30–50% of HIV‐positive patients. Importantly, persistent white matter pathologies, specifically corpus callosum thinning and disruption of white matter microstructures observed in patients with HAND despite viral control through cART, raise the possibility that HIV infection in the setting of suboptimal cART may perturb oligodendrocyte (OL) maturation, function and/or survival, influencing HAND persistence in the cART era. To examine the effect of HIV infection on OL maturation, we used supernatants of primary human monocyte‐derived macrophages infected with HIV (HIV/MDMs) to treat primary cultures of rat oligodendrocyte precursor cells (OPCs) during their differentiation to mature OLs. Using immunostaining for lineage‐specific markers, we found that HIV/MDMs significantly inhibited OPC maturation. Based on our previous studies, we examined the potential role of several signaling pathways, including ionotropic glutamate receptors and the integrated stress response (ISR), and found that AMPA receptors (AMPAR)/kainic acid (KA) receptors (KARs) mediated the HIV/MDMs‐induced defect in OL maturation. We also found that the treatment of OPC cultures with glutamate or AMPAR/KAR agonists phenocopied this effect. Blocking ISR activation, specifically the PERK arm of the ISR, protected OPCs from HIV/MDMs‐mediated inhibition of OL maturation. Further, while glutamate, AMPA, and KA activated the ISR, inhibition of AMPAR/KAR activation prevented ISR induction in OPCs and rescued OL maturation. Collectively, these data identify glutamate signaling via ISR activation as a potential therapeutic pathway to ameliorate white matter pathologies in HAND and highlight the need for further investigation of their contribution to cognitive impairment.

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Section: Methodsmentioning

confidence: 99%

Section: Oligodendrocyte Precursor Cells (Opcs) Differentiate Into Ma...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

Roth

Akay

Grinspan

et al. 2021

Glia

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“…This raises the possibility that this observation is due to a delay in remyelination caused by BIC or reflects a heterogeneous OPC response to injury. Previous work with elvitegravir, in vitro , demonstrated that upon washout of the drug, differentiation was able to proceed normally for one of the concentrations tested (Roth et al, 2021). Thus, it seems possible that BIC-treated, cuprizone fed animals would remyelinate following cessation of BIC treatment.…”

Section: Discussionmentioning

confidence: 94%

Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation

Festa

Clyde

Long

et al. 2022

Preprint

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White matter deficits are a common neuropathologic finding in neurologic disorders, including HIV-associated neurocognitive disorders (HAND). In HAND, the persistence of white matter alterations despite suppressive antiretroviral (ARV) therapy suggests that ARVs may be directly contributing to these impairments. Here, we report that a frontline ARV, bictegravir (BIC), significantly attenuates remyelination following cuprizone-mediated demyelination, a model that recapitulates acute demyelination, but has no impact on already formed mature myelin. Mechanistic studies in vitro revealed that treatment with BIC leads to significant decrease in mature oligodendrocytes accompanied by lysosomal de-acidification and impairment of lysosomal degradative capacity with no alterations in lysosomal membrane permeability or total lysosome number. Activation of the endolysosomal cation channel TRPML1 prevents both lysosomal de-acidification and impairment of oligodendrocyte differentiation by BIC. Lastly, we show that de-acidification of lysosomes by compounds that raise lysosomal pH is sufficient to prevent maturation of oligodendrocytes. Overall, this study has uncovered a critical role for lysosomal acidification in modulating oligodendrocyte function and has implications for neurologic diseases characterized by lysosomal dysfunction and white matter abnormalities.

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“…Indeed, the expression of ISR proteins has been shown to increase in OLN under stress conditions ( Pavitt, 2005 ; Gow and Wrabetz, 2009 ; Clayton et al, 2017 ). In an in culture approach it was recently shown that activation of the ISR resulted in decreased remyelination in a cuprizone model of chemical demyelination ( Roth et al, 2021 ), while Chen et al reported that prolongation of the ISR in combination with exposure to IFN-γ significantly enhanced remyelination by increasing the number of remyelinating oligodendrocytes and myelinated axons ( Chen et al, 2021 ). Changes in energy sources, coupled with changes in global protein synthesis, may explain why ImOL are practically non-existent at the M-OL stage.…”

Section: Adoption Of Immune Proteasome and Hypothesized Effects On Me...mentioning

confidence: 99%

Beyond Myelination: Possible Roles of the Immune Proteasome in Oligodendroglial Homeostasis and Dysfunction

2022

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Oligodendroglia play a critical role in CNS homeostasis by myelinating neuronal axons in their mature stages. Dysfunction in this lineage occurs when early stage OPCs are not able to differentiate to replace dying Mature Myelinating Oligodendrocytes. Many hypotheses exist as to why de- and hypo-myelinating disorders and diseases occur. In this review, we present data to show that oligodendroglia can adopt components of the immune proteasome under inflammatory conditions. The works reviewed further reflect that these immune-component expressing oligodendroglia can in fact function as antigen presenting cells, phagocytosing foreign entities and presenting them via MHC II to activate CD4+ T cells. Additionally, we hypothesize, based on the limited literature, that the adoption of immune components by oligodendroglia may contribute to their stalled differentiation in the context of these disorders and diseases. The present review will underline: (1) Mechanisms of neuroinflammation in diseases associated with Immune Oligodendroglia; (2) the first associations between the immune proteasome and oligodendroglia and the subtle distinctions between these works; (3) the suggested functionality of these cells as it is described by current literature; and (4) the hypothesized consequences on metabolism. In doing so we aim to shed light on this fairly under-explored cell type in hopes that study of their functionality may lead to further mechanistic understanding of hypo- and de-myelinating neuroinflammatory disorders and diseases.

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Differential effects of integrase strand transfer inhibitors, elvitegravir and raltegravir, on oligodendrocyte maturation: A role for the integrated stress response

Cited by 16 publications

References 43 publications

HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation

Beyond Myelination: Possible Roles of the Immune Proteasome in Oligodendroglial Homeostasis and Dysfunction

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