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A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury

Nina Y Yuan1, Kathryn E Medders2, Ana B Sanchez2

  • 1University of California Riverside, School of Medicine, Division of Biomedical Sciences, 900 University Ave, Riverside, CA 92521, USA.

Brain, Behavior, and Immunity
|February 29, 2024
PubMed

Insights

Cysteinyl-leukotrienes (CysLT) released by HIV-infected macrophages mediate neurotoxicity via p38 MAPK. Inhibiting the CysLT pathway protects neurons and improves memory in HIV-associated neuroinflammation models.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by gp120 cause neurotoxicity.
  • p38 mitogen-activated protein kinase (p38 MAPK) signaling is crucial for this MΦ-mediated neurotoxicity.
  • Downstream pathways linking p38 MAPK to neurotoxicity were previously unclear.

Purpose of the Study:

  • To investigate the role of cysteinyl-leukotrienes (CysLT) in HIV-associated neurotoxicity.
  • To identify downstream pathways of p38 MAPK involved in HIV-induced MΦ neurotoxicity.

Main Methods:

  • Utilized siRNA and pharmacological inhibitors for p38 MAPK and CysLT pathway components (LTC4S, CYSLTR1).
  • Assessed neurotoxicity of gp120-stimulated and HIV-infected MΦ on cerebrocortical neurons.
  • Analyzed CysLT pathway gene expression in HIV-infected human brains and a transgenic mouse model (HIVgp120tg).
  • Evaluated neuronal damage and spatial memory in genetically modified HIVgp120tg mice lacking LTC4S or CysLTR1.

Main Results:

  • CysLTs released by MΦ downstream of p38 MAPK critically contribute to neurotoxicity.
  • Inhibition of p38 MAPK reduced MΦ CysLT synthase (LTC4S) expression.
  • Blocking the CysLT receptor 1 (CYSLTR1) protected neurons from MΦ toxicity.
  • CysLT pathway components were dysregulated in HIV-affected brains and the HIVgp120tg model.
  • Genetic deletion of LTC4S or CysLTR1 prevented neuronal damage and spatial memory deficits in HIVgp120tg mice.

Conclusions:

  • Cysteinyl-leukotrienes play a novel and critical role in HIV-associated brain injury.
  • The p38 MAPK-CysLT pathway is a key mediator of neurotoxicity in HIV infection.
  • Targeting the CysLT pathway offers a potential therapeutic strategy for NeuroHIV.
Keywords:
Behavior deficitsCysteinyl leukotrienesERK1/2 signalingHIVHIVgp120-transgenic, HIV associated neurocognitive disorderKnockoutMacrophagesNeurotoxicityP38 MAPK

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