PDF(Pubmed)
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.
摘要：
感染人类免疫缺陷病毒（HIV）-1或被其包膜蛋白gp120激活的巨噬细胞（MΦ）具有神经毒性。我们先前发现，通过p38丝裂原活化蛋白激酶（p38MAPK）的信号传导对于HIVgp120刺激的MΦ的神经毒性至关重要。然而,相关的下游途径仍然难以捉摸。在这里，我们表明，由HIV感染或HIVgp120刺激的p38MAPK下游的MΦ释放的半胱氨酰-白三烯（CysLT）严重有助于神经毒性。siRNA介导的或药理抑制p38MAPK剥夺了CysLT合酶（LTC4S）的MΦ，半胱氨酰-白三烯受体1（CYSLTR1）的药理抑制作用可保护大脑皮层神经元免受gp120刺激和HIV感染的MΦ的毒性。CysLT途径的组分在HIV感染个体的大脑和NeuroHIV的转基因小鼠模型(HIVgp120tg)中被差异调节。此外，LTC4S或CysLTR1的遗传消融可预防HIVgp120tg小鼠的神经元损伤和空间记忆受损。总之,我们的发现提示半胱氨酰-白三烯在HIV相关脑损伤中具有新的关键作用.
