Inositol-requiring enzyme 1 alpha (IRE1α) at the int-ER-section of astrocyte-mediated neurotoxicity: Implications in (METH)amphetamine use and HIV-associated neurocognitive disorders




Proulx, Jessica
Borgmann, Kathleen


0000-0002-5452-0461 (Proulx, Jessica)

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Human immunodeficiency virus 1 (HIV-1) invades the central nervous system (CNS) early during infection and can persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Astrocytes are the most numerous glial cells in the CNS and provide essential support to neurons to ensure CNS health and function. During a neuropathological challenge, such as HIV-1 infection, astrocytes can shift their neuroprotective functions to become neurotoxic and even serve as reservoirs for HIV-1 infection. Indeed, astrocyte-mediated neurotoxicity (astrogliosis) is a hallmark of neurodegenerative diseases and disorders provoking consequences such as neuroinflammation, oxidative stress, and glutamate excitotoxicity. Astrocyte responses that regulate these outcomes include increased release of inflammatory mediators, decreased metabolite and antioxidant provision, and impaired uptake of glutamate from the tripartite synapsis, respectively. Notably, substance use disorders, including (METH)amphetamine are disproportionately elevated among people living with HIV-1. METH use can induce neurotoxic and neurodegenerative consequences, which can increase one's risk and severity of HAND. Identifying cellular and molecular mechanisms underlying astrocyte-mediated neurotoxicity are of heightened importance to optimize the coupling between astrocytes and neurons and ensure neuronal fitness against CNS pathology, including HAND and METH use disorder. Mitochondria are essential organelles for regulating metabolic, antioxidant, and inflammatory profiles. Moreover, endoplasmic reticulum (ER)-associated signaling pathways, such as calcium and the unfolded protein response (UPR), are important messengers for cellular fate and function, including inflammation and mitochondrial homeostasis. Increasing evidence supports that the three arms of the UPR are involved in the direct contact and communication between ER and mitochondria through mitochondria-associated ER membranes (MAMs). Our previous studies in primary human astrocytes demonstrated increased UPR/MAM mediator protein expression following HIV-1 infection or chronic METH exposure, of which, inositol-requiring enzyme 1 alpha (IRE1α) was most prominently elevated. Interestingly, pharmacological inhibition of the three UPR arms, illuminated that IRE1α is a potential regulator of astrocyte mitochondrial respiration. Here, we further delve into the functional role of IRE1α in primary human astrocytes using an IRE1α overexpression plasmid followed by stimulation with proinflammatory cytokine, interleukin 1β (IL-1β). These conditions permit interpretations for both IRE1α expression and activation as IL-1β is a potent activator of ER stress. Our findings confirm IRE1α modulates astrocyte metabolic function, morphological activation, cytokine secretion, and glutamate clearance, highlighting a novel target for regulating astrocyte metabolic and inflammatory phenotypes. Therapeutic targeting of astrocyte IRE1α could help combat astrocyte-mediated neurotoxicity and potentially promote a more neuroprotective phenotype during CNS pathology.


Research Appreciation Day Award Winner - 2022 School of Biomedical Sciences Oral Presentation - 2nd Place