Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
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DOI：
10.1073/pnas.96.14.8212
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发表时间：
1999-07-06
影响因子：
11.1
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Kaul, M;Lipton, SA
HIV-1糖蛋白gp 120在体外和体内诱导啮齿动物和人类神经元的损伤和凋亡，因此被认为有助于HIV相关性痴呆。除了CD 4之外，不同的gp 120分离物分别与α-或β-趋化因子受体CXCR 4和CCR 5结合。这些和其他趋化因子受体位于脑巨噬细胞/小胶质细胞、星形胶质细胞和神经元上。因此，细胞凋亡可以通过gp 120与神经元的直接相互作用，间接通过刺激神经胶质细胞释放神经毒性因子，或通过两种途径发生。在这里，我们展示了大鼠大脑皮层培养物，它概括了通常在大脑中发现的细胞的类型和比例，即，在神经元、星形胶质细胞和巨噬细胞/小胶质细胞中，β-趋化因子RANTES（受激活调节，正常T细胞表达和分泌）和巨噬细胞炎性蛋白（MIP-1 β）保护神经元免受gp 120（SF 2）诱导的凋亡。gp 120（SF 2）分离物偏好结合CXCR 4受体，类似于生理学α-趋化因子配体，基质细胞衍生因子（SDF）-1 α/β。SDP-1 α/β不能防止gp 120（SF 2）神经毒性，事实上还诱导神经元凋亡。我们可以完全废除gp 120（SF 2）诱导的神经元凋亡与三肽TKP，抑制巨噬细胞/小胶质细胞的激活。相比之下，TKP或巨噬细胞/小胶质细胞耗竭不能预防SDF-1神经毒性。抑制p38丝裂原活化蛋白激酶改善了gp 120（SF 2）和SDF-1诱导的神经元凋亡。总之，这些结果表明，gp 120（SF 2）和SDF-1在刺激CXCR 4诱导神经元凋亡的细胞类型上不同，但两种配体都使用p38丝裂原活化蛋白激酶途径进行死亡信号传导。此外，gp 120（SF 2）诱导的神经元凋亡主要依赖于通过激活巨噬细胞/小胶质细胞上的趋化因子受体的间接途径，而SDF-1可能直接作用于神经元或星形胶质细胞。
HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons in vitro and in vivo and is therefore thought to contribute to HIV-associated dementia. In addition to CD4, different gp120 isolates bind to the alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine receptors are on brain macrophages/microglia, astrocytes, and neurons. Thus, apoptosis could occur via direct interaction of gp120 with neurons, indirectly via stimulation of glia to release neurotoxic factors, or via both pathways. Here we show in rat cerebrocortical cultures that recapitulate the type and proportion of cells normally found in brain, i.e., neurons, astrocytes, and macrophages/microglia, that the beta-chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP-1 beta) protect neurons from gp120(SF2)-induced apoptosis. The gp120(SF2) isolate prefers binding to CXCR4 receptors, similar to the physiological alpha-chemokine ligands, stromal cell-derived factor (SDF)-1 alpha/beta. SDP-1 alpha/beta failed to prevent gp120(SF2) neurotoxicity, and in fact also induced neuronal apoptosis. We could completely abrogate gp120(SF2)-induced neuronal apoptosis with the tripeptide TKP, which inhibits activation of macrophages/microglia. In contrast, TKP or depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity. Inhibition of p38 mitogen-activated protein kinase ameliorated both gp120(SF2)- and SDF-1-induced neuronal apoptosis, Taken together, these results suggest that gp120(SF2) and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein kinase pathway for death signaling. Moreover, gp120(SF2)-induced neuronal apoptosis depends predominantly on an indirect pathway via activation of chemokine receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or astrocytes.