Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat-induced inflammatory M1 phenotype in microglial cells.
Douglas Bardini SilveiraMonique Ferrary AméricoNatália Porto FloresHernán TerenziAguinaldo Roberto PintoPublished in: Cell biochemistry and function (2022)
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.
Keyphrases
- antiretroviral therapy
- hiv infected
- endoplasmic reticulum stress
- endoplasmic reticulum
- induced apoptosis
- inflammatory response
- hiv positive
- lipopolysaccharide induced
- human immunodeficiency virus
- lps induced
- hiv infected patients
- hiv aids
- cell cycle arrest
- hiv testing
- hepatitis c virus
- protein kinase
- oxidative stress
- signaling pathway
- cell proliferation
- binding protein
- neuropathic pain
- randomized controlled trial
- bipolar disorder
- south africa
- rheumatoid arthritis
- spinal cord
- traumatic brain injury
- immune response
- pi k akt
- drug induced
- spinal cord injury
- toll like receptor
- dendritic cells
- transcription factor
- nitric oxide
- protein protein