HIV-1 gp120 Promotes Lysosomal Exocytosis in Human Schwann Cells
HIV-1 gp120 Promotes Lysosomal Exocytosis in Human Schwann Cells
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DOI：
10.3389/fncel.2019.00329
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发表时间：
2019-07-17
影响因子：
5.3
通讯作者：
Chen, Xuesong
中科院分区：
文献类型：
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作者：
Datta, Gaurav;Miller, Nicole M.;Chen, Xuesong
人类免疫缺陷病毒1型（HIV-1）相关神经病变是HIV-1最常见的神经系统并发症，伴随着影响生活质量的衰弱性疼痛。HIV-1 gp 120通过直接的神经毒性作用或间接的促炎反应在HIV神经病变的发病机制中起重要作用。研究表明，gp 120诱导的介质从雪旺细胞释放诱导CCR 5依赖性DRG神经毒性，然而，CCR 5拮抗剂未能改善HIV感染个体的疼痛。因此，迫切需要更好地了解神经病理性疼痛的发病机制，并制定有效的治疗策略。由于许旺细胞中的溶酶体胞吐作用是调节髓鞘形成和脱髓鞘的一个不可或缺的过程，我们确定了gp 120影响人许旺细胞中溶酶体胞吐作用的程度。我们证明，gp 120促进溶酶体向质膜的运动，诱导溶酶体胞吐，并增加ATP释放到细胞外介质。从机制上讲，我们证明了溶酶体去酸化，P2 X4和VNUT的激活是gp 120诱导的溶酶体胞吐的基础。在功能上，我们证明了GP 120诱导的溶酶体胞吐和释放的ATP从雪旺细胞导致细胞内钙离子的增加和产生的胞质活性氧在DRG神经元。我们的研究结果表明，gp 120诱导的溶酶体胞吐和释放ATP从雪旺细胞和DRG神经元有助于HIV-1相关神经病变的发病机制。
Human immunodeficiency virus type 1 (HIV-1) associated neuropathy is the most common neurological complication of HIV-1, with debilitating pain affecting the quality of life. HIV-1 gp120 plays an important role in the pathogenesis of HIV neuropathy via direct neurotoxic effects or indirect pro-inflammatory responses. Studies have shown that gp120-induced release of mediators from Schwann cells induce CCR5-dependent DRG neurotoxicity, however, CCR5 antagonists failed to improve pain in HIV- infected individuals. Thus, there is an urgent need for a better understanding of neuropathic pain pathogenesis and developing effective therapeutic strategies. Because lysosomal exocytosis in Schwann cells is an indispensable process for regulating myelination and demyelination, we determined the extent to which gp120 affected lysosomal exocytosis in human Schwann cells. We demonstrated that gp120 promoted the movement of lysosomes toward plasma membranes, induced lysosomal exocytosis, and increased the release of ATP into the extracellular media. Mechanistically, we demonstrated lysosome de-acidification, and activation of P2X4 and VNUT to underlie gp120-induced lysosome exocytosis. Functionally, we demonstrated that gp120-induced lysosome exocytosis and release of ATP from Schwann cells leads to increases in intracellular calcium and generation of cytosolic reactive oxygen species in DRG neurons. Our results suggest that gp120-induced lysosome exocytosis and release of ATP from Schwann cells and DRG neurons contribute to the pathogenesis of HIV-1 associated neuropathy.