Inhibiting IRE-1 RNase signaling decreases HIV-1 Tat-induced inflammatory M1 state in microglial cells.

Aguinaldo Roberto Pinto, Monique Ferrary Américo, Hernán Terenzi, Douglas Bardini Silveira

Biochimica et biophysica acta. General subjects 2022 Nov

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HIV-1 transactivator (Tat) protein plays a critical role in neurological disorders resulting from viral infection, commonly known as HIV-1-associated neurocognitive disorders (HAND). Previous studies have shown that circulant Tat induces M1 microglial activation, one of the hallmark features of HAND, and this is coupled with ER stress and subsequent Unfolded Protein Response (UPR) triggering. Here, we demonstrate that bystander stimuli of Tat in microglial cells result in the simultaneous overexpression of IRE1-related markers and production of M1-typed proinflammatory mediators. We also show that blocking IRE1/XBP-1 signaling using 4μ8C diminishes such inflammatory response. These findings reinforce a role for the IRE1/XBP-1 pathway in HIV-1 Tat neuropathology and suggest that targeting IRE1 RNase activity using 4μ8C or analogue compounds may provide a therapeutic intervention to mitigate against neuroinflammation in HAND. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Aguinaldo Roberto Pinto, Monique Ferrary Américo, Hernán Terenzi, Douglas Bardini Silveira. Inhibiting IRE-1 RNase signaling decreases HIV-1 Tat-induced inflammatory M1 state in microglial cells. Biochimica et biophysica acta. General subjects. 2022 Nov;1866(11):130219