Abstract
Under physiological conditions, the function of astrocytes in providing brain metabolic support is compromised under pathophysiological conditions caused by human immunodeficiency virus (HIV) and opioids. Herein, we examined the role of autophagy, a lysosomal degradation pathway important for cellular homeostasis and survival, as a potential regulatory mechanism during pathophysiological conditions in primary human astrocytes. Blocking autophagy with small interfering RNA (siRNA) targeting BECN1, but not the Autophagy-related 5 (ATG5) gene, caused a significant decrease in HIV and morphine-induced intracellular calcium release. On the contrary, inducing autophagy pharmacologically with rapamycin further enhanced calcium release and significantly reverted HIV and morphine-decreased glutamate uptake. Furthermore, siBeclin1 caused an increase in HIV-induced nitric oxide (NO) release, while viral-induced NO in astrocytes exposed to rapamycin was decreased. HIV replication was significantly attenuated in astrocytes transfected with siRNA while significantly induced in astrocytes exposed to rapamycin. Silencing with siBeclin1, but not siATG5, caused a significant decrease in HIV and morphine-induced interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) release, while secretion of IL-8 was significantly induced with rapamycin. Mechanistically, the effects of siBeclin1 in decreasing HIV-induced calcium release, viral replication, and viral-induced cytokine secretion were associated with a decrease in activation of the nuclear factor kappa B (NF-κB) pathway.
Highlights
Astrocytes are the most abundant cell type in the central nervous system (CNS) and contribute to a variety of tasks, ranging from buffering calcium release and glutamate uptake [1,2,3], to regulating brain immune response [4] and controlling the blood-brain barrier (BBB) and blood flow [5]
We investigated the role of the autophagy pathway as a possible molecular mechanism responsible for regulating intracellular calcium release, glutamate uptake and release of reactive oxygen and nitrogen species in astrocytes during pathological conditions with human immunodeficiency virus (HIV) and morphine
We examined the mechanistic role of autophagy in regulating HIV replication and HIV and morphine-induced inflammatory cytokines in astrocytes
Summary
Astrocytes are the most abundant cell type in the central nervous system (CNS) and contribute to a variety of tasks, ranging from buffering calcium release and glutamate uptake [1,2,3], to regulating brain immune response [4] and controlling the blood-brain barrier (BBB) and blood flow [5]. Since astrocyte dysfunction is a severe neuropathological finding of HIV-associated encephalitis, it can be reasoned that astrocyte activation leads to impaired astrocyte-neuron networks, contributing to apoptosis of neurons [11]. It is commonly understood that HIV-associated neurological disorders are caused in part by astrocytic dysfunction [12]. Further complication with opiate drug abuse (e.g., morphine), a frequent comorbidity of HIV infection [3,4,5,6,7,8,9,10,11,12,13,14], is known to amplify HIV-induced dysfunctions in astrocytes [13,14,15,16,17]. Evidence has proven the important role of astrocytes in HIV and morphine-induced neurological disorders, elucidating a potential molecular mechanism(s) by which HIV-infected astrocytes affect brain homeostasis and regulate neuro-inflammation are still of great interest
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