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Published on: September 19, 2010
Hydrogen Sulfide Rescues Microglia From HIV Tat-Driven Ferroptosis: Implications for HIV-Associated Neuroinflammation
Aitizaz Ul Ahsan1, Frida L Martínez-Cuevas1, Elias Horanieh1
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Aim:
HIV transactivator of transcription (Tat) protein induces oxidative stress, neuroinflammation, and glial dysfunction in NeuroHIV. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a contributor to HIV-associated neurocognitive disorders. This study aimed to determine whether hydrogen sulfide (H2S) mitigates HIV Tat-induced ferroptosis in microglial cells.
Methods:
BV2 microglial cells were pretreated with sodium hydrosulfide (NaHS; 100 μM), an H2S donor, followed by exposure to recombinant HIV Tat (100 ng/mL, 48 h). Ferroptotic indices, including cytosolic Fe2+ accumulation, lipid peroxidation, reactive oxygen species (ROS) generation, and cell membrane damage, were assessed using fluorescence-based assays and lactate dehydrogenase (LDH) release. Expression of ferroptosis-related and antioxidant proteins was analyzed by western blotting, and proinflammatory cytokine release was quantified by qPCR.
Results:
NaHS pretreatment significantly attenuated HIV Tat-induced Fe2+ accumulation, ROS generation, lipid peroxidation, and LDH release. Mechanistically, NaHS suppressed pro-ferroptotic mediators, acyl-CoA synthetase long-chain family member 4 (ACSL4) and 4-hydroxynonenal (4-HNE), while restoring solute carrier family 7-member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. NaHS also reduced HIV Tat-induced IL1β, IL6, and TNFα secretion.
Conclusion:
These findings demonstrate that H2S protects HIV Tat-exposed microglia by suppressing ferroptosis and restoring cellular homeostasis. Collectively, these results identify H2S signaling as a promising mechanistic target for further investigation in NeuroHIV-associated neuroinflammation.
Insights
Hydrogen sulfide (H2S) protects microglia from HIV Tat-induced ferroptosis, a cell death pathway implicated in NeuroHIV. This study shows H2S mitigates oxidative stress and inflammation, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- HIV-associated neurocognitive disorders (HAND) involve neuroinflammation and glial dysfunction.
- Ferroptosis, a form of iron-dependent cell death, contributes to HAND pathogenesis.
- Oxidative stress induced by HIV transactivator of transcription (Tat) protein is a key factor in NeuroHIV.
Purpose of the Study:
- To investigate the protective role of hydrogen sulfide (H2S) against HIV Tat-induced ferroptosis in microglial cells.
- To determine if H2S can mitigate oxidative stress, lipid peroxidation, and inflammation in the context of NeuroHIV.
Main Methods:
- BV2 microglial cells were treated with an H2S donor (NaHS) followed by exposure to HIV Tat protein.
- Ferroptosis markers (Fe2+ accumulation, lipid peroxidation, ROS, LDH release) were measured.
- Protein and cytokine expression related to ferroptosis and inflammation were analyzed.
Main Results:
- H2S treatment significantly reduced Tat-induced ferroptosis markers, including Fe2+ accumulation, ROS generation, and lipid peroxidation.
- H2S suppressed pro-ferroptotic proteins (ACSL4, 4-HNE) and restored anti-ferroptotic proteins (SLC7A11, GPX4).
- H2S attenuated the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) induced by HIV Tat.
Conclusions:
- Hydrogen sulfide (H2S) effectively protects microglia from HIV Tat-induced ferroptosis.
- H2S signaling restores cellular homeostasis and reduces neuroinflammation in a model of NeuroHIV.
- H2S represents a promising therapeutic target for managing NeuroHIV-associated neuroinflammation.
