2024-04-04 カリフォルニア大学リバーサイド校(UCR)
<関連情報>
- https://news.ucr.edu/articles/2024/04/04/small-protein-plays-big-role-chronic-hiv-infection
- https://www.sciencedirect.com/science/article/pii/S0889159124002599
- https://www.sciencedirect.com/science/article/pii/S0889159124002502
HIV-1による神経細胞傷害におけるマクロファージ由来システイニルロイコトリエンの重要な役割 A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury
Nina Y. Yuan, Kathryn E. Medders, Ana B. Sanchez, Rohan Shah, Cyrus M. de Rozieres, Daniel Ojeda-Juárez, Ricky Maung, Roy Williams, Benjamin B. Gelman, Bas J. Baaten, Amanda J. Roberts, Marcus Kaul
Brain, Behavior, and Immunity Available online:27 February 2024
DOI:https://doi.org/10.1016/j.bbi.2024.02.023
Highlights
- The CYSLTR1 antagonist montelukast protects neurons from macrophage neurotoxicity induced by HIV-1 or HIVgp120 protein.
- HIV-1 infection or exposure to HIVgp120 increases CysLT release by macrophages and inhibition of p38 MAPK abrogates elevated CysLT production.
- Cerebral cortex of HIV+ individuals with pathology expresses more CYSLTR1 than that of HIV+ persons without pathology or uninfected individuals.
- Genetic ablation of Ltc4s or Cysltr1 in HIVgp120-transgenic mice results in complete neuroprotection and preserved memory function.
- Genetic ablation of Ltc4s or Cysltr1 in mice reveals a physiological role of CysLTs in memory function and sexual dimorphisms in glial cells.
Abstract
Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.
インターフェロンβ欠乏は、トランスジェニックNeuroHIVモデルにおける慢性HIV-1エンベロープタンパク質曝露に対する脳の反応を変化させる Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV
Hina Singh, Jeffrey Koury, Ricky Maung, Amanda J. Roberts, Marcus Kaul
Brain, Behavior, and Immunity Available online:13 February 2024
DOI:https://doi.org/10.1016/j.bbi.2024.02.014
Highlights
- Genetic ablation of IFNβ modulates HIVgp120-induced neuropathology in a sex-dependent fashion.
- Endogenous IFNβ is required for normal function of spatial and recognition memory.
- Genetic ablation of IFNβ aggravates impairment of spatial memory in the presence of HIVgp120.
- Endogenous IFNβ regulates expression of neuroinflammatory factors induced during exposure to HIVgp120.
- Genetic ablation of IFNβ alters expression of neurotransmission-related genes in a sex-dependent fashion.
Abstract
Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.
