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HIV-1 Tat-induced microglial activation and neuronal damage is inhibited via CD45 modulation: A potential new
Abstract:
Microglia become activated in humans subsequent to infection with HIV, and uncontrolled brain inflammation plays a key role in neuronal injury and and cognitive dysfunction during HIV infection. Various studies have shown a deleterious role for the HIV regulatory protein Tat in the development and maintenance of HIV-associated neurocognitive disorders (HAND). One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine phosphatase (PTP), CD45. It is especially effective at inhibiting microglial activation because its action takes place far upstream from proinflammatory intracellular signaling mediators. To investigate the possible role of CD45 in microglial responsiveness to HIV-1 Tat protein, we treated BV-2 microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1, 10-phenanthroline) oxovanadate (phen), 5 μM] and HIV-1 Tat protein (700ng/ml). We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) release, both of which were dependent on p44/42 mitogen-activated protein kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibited these Tat or Tat/Phen effects via attenuation of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a validation of these findings in vivo, brains from transgenic mice deficient for CD45 through complete genetic ablation, or by CNS delivery of CD45shRNA, demonstrate markedly increased production of TNF-α 24 hours after intracerebroventricular injection of HIV-Tat protein (5μg/mouse) compared to control mice. This increased microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be effective in suppressing microglial activation associated with HAND.
Insights
CD45 protein inhibits microglial activation, a key factor in HIV-associated neurocognitive disorders (HAND). Activating CD45 may offer a therapeutic strategy to reduce brain inflammation and neuronal injury in HAND patients.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- HIV infection triggers microglial activation, leading to brain inflammation, neuronal injury, and cognitive dysfunction in HIV-associated neurocognitive disorders (HAND).
- The HIV regulatory protein Tat exacerbates HAND development and progression.
- CD45, a protein-tyrosine phosphatase (PTP), is known to inhibit microglial activation upstream of inflammatory signaling pathways.
Purpose of the Study:
- To investigate the role of CD45 in regulating microglial activation in response to HIV-1 Tat protein.
- To explore the potential of targeting CD45 signaling for therapeutic intervention in HAND.
Main Methods:
- BV-2 microglia were treated with HIV-1 Tat protein and a tyrosine phosphatase inhibitor (phen).
- Microglial activation was assessed by measuring tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) release, and p44/42 mitogen-activated protein kinase (MAPK) activation.
- The effect of anti-CD45 antibody stimulation on Tat-induced microglial activation was evaluated.
- In vivo studies utilized CD45-deficient transgenic mice treated with HIV-Tat protein to assess TNF-α production, astrogliosis, and neuronal apoptosis.
Main Results:
- Combined treatment with Tat and a phosphatase inhibitor synergistically increased pro-inflammatory cytokine release (TNF-α, IL-1β) via p44/42 MAPK activation.
- Stimulation of CD45 with an antibody significantly inhibited Tat-induced microglial activation by attenuating p44/42 MAPK signaling.
- CD45-deficient mice exhibited increased TNF-α production, astrogliosis, and cortical neuron loss following HIV-Tat protein administration compared to controls.
Conclusions:
- CD45 negatively regulates microglial activation in response to HIV-1 Tat.
- Targeting CD45 PTP signaling represents a potential therapeutic strategy for suppressing microglial activation and mitigating neuronal damage in HAND.
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