Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Brain Behav Immun. 2020 Aug;88:325-339. doi: 10.1016/j.bbi.2020.03.027. Epub 2020 Mar 27.
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. In in vitro cell 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.
人类免疫缺陷病毒 1 型（HIV-1）衣壳蛋白，如糖蛋白 120（gp120），对神经炎症反应负责，被认为是 HIV 相关远端感觉神经病的原因。越来越多的证据表明，T 细胞系嗜性 X4 gp120 增加了巨噬细胞向周围神经的浸润，从而引发神经炎症导致疼痛。然而，X4 gp120 诱导巨噬细胞募集到周围神经系统的机制尚不清楚。在这里，我们证明了 HIV-1 株 IIIB 和 MN 的 X4 gp120 经周围神经给药会引起小鼠机械性过敏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，gp120 IIIB 或 MN 给药后 7 天，骨髓来源的巨噬细胞更多地浸润到坐骨神经和背根神经节（DRG）实质中。使用氯膦酸盐脂质体化学清除循环中的巨噬细胞，显著抑制了 gp120 IIIB 诱导的疼痛样行为。在体外细胞浸润分析中，RAW 264.7 细胞（一种鼠巨噬细胞系）被 gp120 IIIB 或 MN 处理的培养雪旺细胞的条件培养基趋化，而不是被这些 gp120 处理的 DRG 神经元的条件培养基趋化，这表明雪旺细胞衍生的可溶性因子可能参与了巨噬细胞浸润。我们通过基因表达谱分析发现，趋化因子 CXCL1 是巨噬细胞和中性粒细胞的趋化因子，在 gp120 IIIB 处理的培养雪旺细胞中增加。类似于 gp120 IIIB 或 MN，周围神经给予重组 CXCL1 会引起疼痛样行为，并伴有巨噬细胞浸润到周围神经。此外，重复注射 CXCR2（CXCL1 受体）拮抗剂或 CXCL1 中和抗体可防止 gp120 IIIB 处理的小鼠出现疼痛样行为和巨噬细胞浸润。因此，本研究新定义了 Schwann 细胞衍生的 CXCL1，它是对 X4 gp120 暴露的反应而分泌的，负责巨噬细胞浸润到周围神经，并与小鼠的疼痛样行为有关。我们在此提出 Schwann 细胞与巨噬细胞之间的通讯可能在诱导 X4 HIV-1 相关疼痛中起重要作用。
