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  • Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat-induced inflammatory M1 phenotype in microglial cells.

Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat-induced inflammatory M1 phenotype in microglial cells.

Cell biochemistry and function (2022-01-20)
Douglas Bardini Silveira, Monique Ferrary Américo, Natália Porto Flores, Hernán Terenzi, Aguinaldo Roberto Pinto
ABSTRACT

HIV-1-associated neurocognitive disorders (HAND) are a major concern in HIV-infected individuals despite the currently available antiretroviral therapy regime. Impaired M1 pro-inflammatory microglial activation is considered one of the hallmark features of HAND neuropathogenesis, and it has been suggested that circulant HIV-1 transactivator protein (Tat) can play a critical role in this process. At the same time, endoplasmatic reticulum (ER) stress has also been implicated in neurodegenerative conditions resulting from the accumulation of misfolded proteins and subsequent unfolded protein response (UPR) deflagration. Here, we demonstrate that pharmacological inhibition of UPR-related protein kinase R-like endoplasmic reticulum kinase (PERK) can attenuate HIV-1 Tat-induced M1 inflammatory state in microglia in vitro. Our initial experiments demonstrate that the bystander stimulus of recombinant Tat on BV-2 microglial cells result in the coupled overexpression of central UPR markers and pro-inflammatory mediators such as iNOS, surface CD16/32 and secreted tumour necrosis factor-α (TNF-α), IL-6, monocyte chemoattractant protein (MCP)-1 and NO. We show that blocking PERK-eIF2-α-ATF4 signalling using the PERK inhibitor GSK2606414 leads to reduced inflammatory response in M1-like BV-2 cells activated by recombinant Tat. Taken together, these findings suggest that PERK targeting may provide a therapeutic intervention to mitigate against lasting neuroinflammation and neuronal loss in of HAND.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody
Sigma-Aldrich
Anti-Mouse IgG (Fc specific)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution