Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways
Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways
复制标题
DOI：
10.1189/jlb.0503206
复制
发表时间：
2003-11-01
影响因子：
5.5
通讯作者：
Collman, RG
中科院分区：
文献类型：
--
作者：
Lee, C;Liu, QH;Collman, RG
巨噬细胞是人类免疫缺陷病毒1型（HIV-1）感染的主要靶点。除了它们作为生产性病毒储库的作用外，感染和未感染的巨噬细胞的不适当活化似乎有助于发病机制。HIV-1感染需要病毒包膜表面糖蛋白gp 120、细胞表面蛋白CD 4和趋化因子受体CCR 5或CXCR 4之间的初始相互作用。除了它们在HIV-1进入中的作用外，CCR 5和CXCR 4是G蛋白偶联受体，可以激活多种细胞内信号通路。HIV-1 gp 120已被证明通过几种细胞类型中的趋化因子受体激活信号通路，包括淋巴细胞、神经元和星形胶质细胞。在某些细胞类型中，这些后果可能导致细胞损伤。在这篇综述中，我们强调我们的数据表明，不同的信号发生在初级人类巨噬细胞响应gp 120/趋化因子受体的相互作用。这些反应包括K+、Cl-和非选择性阳离子电流，细胞内Ca 2+增加，以及包括粘着斑相关酪氨酸激酶Pyk 2、促分裂原活化蛋白激酶（MAPK）在内的几种激酶的活化。和磷酸肌醇-3激酶。MAPK的激活导致gp 120诱导的趋化因子如单核细胞趋化蛋白-1和巨噬细胞炎性蛋白-1 β以及促炎细胞因子肿瘤坏死因子α的表达。这些反应建立了一个复杂的细胞因子网络，可以增强或抑制HIV-1的复制。此外，gp 120/趋化因子受体信号传导引起的巨噬细胞功能失调可能导致局部炎症和损伤，并进一步招募额外的炎症和/或靶细胞。靶向这些细胞信号通路可能有助于控制HIV感染的炎症后遗症，如神经系统疾病。J. Leukoc. 74：676-682; 2003.
Macrophages are major targets for infection by human immunodeficiency virus type 1 (HIV-1). In addition to their role as productive viral reservoirs, inappropriate activation of infected and uninfected macrophages appears to contribute to pathogenesis. HIV-1 infection requires initial interactions between the viral envelope surface glycoprotein gp120, the cell-surface protein CD4, and a chemokine receptor CCR5 or CXCR4. Besides their role in HIV-1 entry, CCR5 and CXCR4 are G protein-coupled receptors that can activate multiple intracellular signaling pathways. HIV-1 gp120 has been shown to activate signaling pathways through the chemokine receptors in several cell types including lymphocytes, neurons, and astrocytes. In some cell types, these consequences may cause cellular injury. In this review, we highlight our data demonstrating diverse signaling events that occur in primary human macrophages in response to gp120/chemokine receptor interactions. These responses include K+, Cl-, and nonselective cation currents, intracellular Ca2+ increases, and activation of several kinases including the focal adhesion-related tyrosine kinase Pyk2, mitogen-activated protein kinases (MAPK)., and phosphoinositol-3 kinase. Activation of the MAPK leads to gp120-induced expression of chemokines such as monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1beta and the proinflammatory cytokine tumor necrosis factor alpha. These responses establish a complex cytokine network, which may enhance or suppress HIV-1 replication. In addition, dysregulation of macrophage function by gp120/chemokine receptor signaling may contribute to local inflammation and injury and further recruit additional inflammatory and/or target cells. Targeting these cellular signaling pathways may have benefit in controlling inflammatory sequelae of HIV infection such as in neurological disease. J. Leukoc. Biol. 74:676-682; 2003.