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首页> 外文期刊>Journal of neuroinflammation >Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator
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Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator

机译：HIV-1相关痴呆症中神经毒性辅因子CXCL-10的编程：PKC激活剂在体外消除CXCL-10诱导的神经胶质毒性

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Background More than 50% of patients undergoing lifelong suppressive antiviral treatment for HIV-1 infection develop minor HIV-1-associated neurocognitive disorders. Neurological complications during HIV-1 infection are the result of direct neuronal damage by proinflammatory products released from HIV-1-infected or -uninfected activated lymphocytes, monocytes, macrophages, microglia and astrocytes. The specific pro-inflammatory products and their roles in neurotoxicity are far from clear. We investigated proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of HIV-demented (HIV-D) and HIV-nondemented (HIV-ND) patients and studied their affect on neuroglial toxicity. Methods and results Bioplex array showed elevated levels of signatory chemokines or cytokines (IL-6, IFN-γ, CXCL10, MCP-1 and PDGF) in the CSF of HIV-D patients (n = 7) but not in that of HIV-ND patients (n = 7). Among the signatory cytokines and chemokines, CXCL10 was distinctly upregulated in-vitro in HIV-1 (NLENG1)-activated human fetal astrocytes, HIV-1 (Ba-L)-infected macrophages, and HIV-1 (NLENG1)-infected lymphocytes. Virus-infected macrophages also had increased levels of TNF-α. Consistently, human fetal astrocytes treated with HIV-1 and TNF-α induced the signatory molecules. CXCL10 in combination with HIV-1 synergistically enhanced neuronal toxicity and showed chemotactic activity (~ 40 fold) for activated peripheral blood mononuclear cells (PBMC), suggesting the intersection of signaling events imparted by HIV-1 and CXCL10 after binding to their respective surface receptors, CXCR4 and CXCR3, on neurons. Blocking CXCR3 and its downstream MAP kinase (MAPK) signaling pathway suppressed combined CXCL10 and HIV-1-induced neurotoxicity. Bryostatin, a PKC modulator and suppressor of CXCR4, conferred neuroprotection against combined insult with HIV-1 and CXCL10. Bryostatin also suppressed HIV-1 and CXCL10-induced PBMC chemotaxis. Although, therapeutic targeting of chemokines in brain may have adverse consequences on the host, current findings and earlier evidence suggest that CXCL10 could strongly impede neuroinflammation. Conclusion We have demonstrated induction of CXCL10 and other chemokines/cytokines during HIV-1 infection in the brain, as well as synergism of CXCL10 with HIV-1 in neuronal toxicity, which was dampened by bryostatin.
机译：背景技术接受针对HIV-1感染的终身抑制性抗病毒治疗的患者中，有50％以上会发展为与HIV-1相关的轻度神经认知障碍。 HIV-1感染期间的神经系统并发症是由感染HIV-1或未感染的活化淋巴细胞，单核细胞，巨噬细胞，小胶质细胞和星形胶质细胞释放的促炎产品直​​接对神经元造成损害的结果。特定的促炎产物及其在神经毒性中的作用尚不清楚。我们调查了HIV痴呆（HIV-D）和HIV非痴呆（HIV-ND）患者的脑脊液（CSF）中的促炎细胞因子和趋化因子，并研究了它们对神经胶质毒性的影响。方法和结果Bioplex阵列显示，HIV-D患者（n = 7）的脑脊液中签名趋化因子或细胞因子（IL-6，IFN-γ，CXCL10，MCP-1和PDGF）的水平升高，但在HIV-D患者的脑脊液中却没有升高ND患者（n = 7）。在标志性细胞因子和趋化因子中，CXCL10在HIV-1（NLENG1）激活的人胎儿星形胶质细胞，HIV-1（Ba-L）感染的巨噬细胞和HIV-1（NLENG1）感染的淋巴细胞中明显上调了体外。病毒感染的巨噬细胞也具有增加的TNF-α水平。一致地，用HIV-1和TNF-α处理的人胎儿星形胶质细胞诱导了信号分子。 CXCL10与HIV-1协同增强神经元毒性，对活化的外周血单个核细胞（PBMC）表现出趋化活性（〜40倍），表明HIV-1和CXCL10结合各自的表面受体后所传递的信号事件相交，CXCR4和CXCR3，位于神经元上。阻断CXCR3及其下游MAP激酶（MAPK）信号通路可抑制CXCL10和HIV-1诱导的神经毒性的联合作用。 Bryostatin，一种PKC调节剂和CXCR4的抑制剂，赋予了针对HIV-1和CXCL10联合损伤的神经保护作用。 Bryostatin还抑制HIV-1和CXCL10诱导的PBMC趋化性。尽管针对脑中趋化因子的治疗性靶向可能会对宿主产生不利影响，但目前的发现和早期证据表明CXCL10可以强烈阻碍神经炎症。结论我们证明了在大脑中HIV-1感染过程中CXCL10和其他趋化因子/细胞因子的诱导作用，以及CXCL10与HIV-1在神经元毒性中的协同作用，而这种抑制作用被溴抑他汀抑制。

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