Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice
Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice
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DOI：
10.1016/j.bbi.2020.03.027
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发表时间：
2020-08-01
影响因子：
15.1
通讯作者：
Matsubara，Kazuo
中科院分区：
文献类型：
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作者：
Ntogwa，Mpumelelo;Imai，Satoshi;Matsubara，Kazuo
对人类免疫缺陷病毒1型（HIV-1）外壳蛋白（如糖蛋白120（gp 120））的神经炎症反应被认为是HIV相关远端感觉神经病变的原因。越来越多的证据表明，T细胞系嗜性X4 gp 120增加巨噬细胞浸润到周围神经，从而诱导神经炎症导致疼痛。然而，X4 gp 120诱导巨噬细胞募集到周围神经系统的机制仍不清楚。在这里，我们证明了神经周围应用来自HIV-1株IIIB和MN的X4 gp 120引起小鼠的机械超敏反应和自发性疼痛样行为。此外，流式细胞术和免疫组织化学研究显示，在gp 120 IIIB或MN应用后7天，骨髓源性巨噬细胞向坐骨神经和背根神经节（DRG）实质中的浸润增加。化学删除循环巨噬细胞使用氯膦酸盐脂质体显着抑制gp 120 IIIB诱导的疼痛样行为。在体外细胞浸润分析中，RAW 264.7细胞（鼠巨噬细胞系）是chemoattractive条件培养基从gp 120 IIIB或MN处理培养的雪旺细胞，但不从这些gp 120处理的DRG神经元的条件培养基，表明可能参与雪旺细胞衍生的可溶性因子在巨噬细胞浸润。我们确定使用基因表达阵列，CXCL 1，巨噬细胞和中性粒细胞的趋化因子，增加在gp 120 IIIB处理培养的雪旺细胞。类似于gp 120 IIIB或MN，神经周围应用重组CXCL 1引起疼痛样行为，伴随着巨噬细胞浸润到周围神经。此外，重复注射CXCR 2（CXCL 1受体）拮抗剂或CXCL 1中和抗体可预防gp 120 IIIB治疗小鼠的疼痛样行为和巨噬细胞浸润。因此，本研究新定义了雪旺细胞衍生的CXCL 1，响应于X4 gp 120暴露而分泌，负责巨噬细胞浸润到外周神经中，从而与小鼠的疼痛样行为相关。我们在此提出，许旺细胞和巨噬细胞之间的通信可能在诱导X4 HIV-1相关疼痛中发挥重要作用。
The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins, such as glycoprotein 120 (gp120), are considered to be responsible for the HIV-associated distal sensory neuropathy. Accumulating evidences suggest that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. Here, we demonstrated that perineural application of X4 gp120 from HIV-1 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. Inin vitrocell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB- or MN-treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB-treated cultured Schwann cells. Similar to gp120 IIIB or MN, perineural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore, the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB-treated mice. Thus, the present study newly defines that Schwann cell-derived CXCL1, secreted in response to X4 gp120 exposure, is responsible for macrophage infiltration into peripheral nerves, and is thereby associated with pain-like behaviors in mice. We propose herein that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.