High mobility group box-1 induces pro-inflammatory signaling in human nucleus pulposus cells via toll-like receptor 4-dependent pathway.
High mobility group box-1 induces pro-inflammatory signaling in human nucleus pulposus cells via toll-like receptor 4-dependent pathway.
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DOI：
10.1002/jor.24154
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Chahine NO
中科院分区：
文献类型：
--
作者：
Shah BS;Burt KG;Jacobsen T;Fernandes TD;Alipui DO;Weber KT;Levine M;Chavan SS;Yang H;Tracey KJ;Chahine NO
椎间盘（IVD）退变（DD）与腰痛相关，腰痛是全球残疾的主要原因。导致炎症和触发DD的损伤相关分子模式（DAMP）尚未得到很好的表征。细胞外高迁移率族蛋白-1（HMGB1）蛋白在免疫系统中被认为是一种有效的DAMP和促炎刺激物。在这项研究中，我们发现，HMGB1和IL-6水平增加，在晚期DD患者相比，早期DD。本研究进一步验证了HMGB1促进人类髓核（NP）细胞和组织中驱动DD的炎症信号传导的假设。免疫荧光和蛋白质印迹分析证实了HMGB1的表达及其在细胞应激下由NP细胞释放到细胞外。基因表达和蛋白定量表明，HMGB1刺激表达IL-6和MMP-1的剂量依赖性的方式。使用小分子抑制剂检查了Toll样受体（TLR）-2，-4和晚期糖基化终产物受体（EGFR）作为介导HMGB1信号传导的受体的贡献。用TAK-242抑制TLR-4信号传导完全消除了HMGB1诱导的IL-6和MMP-1表达，而用O-香草醛抑制TLR-2或用FPS-ZM 1抑制TLR-2具有轻度抑制作用。HMGB1刺激激活NF-κ B信号通路，而TAK-242联合处理则消除了该信号通路。最后，在人NP细胞的三维培养系统中评价了HMGB1对基质沉积的影响。这些结果暗示HMGB1是促进NP细胞中的炎症和NP组织降解的有效DAMP。TLR4-HMGB1轴是缓解椎间盘炎症和缓解DD的潜在主要途径。
Intervertebral disc (IVD) degeneration (DD) is associated with low back pain, the leading cause of disability worldwide. Damage-associated molecular patterns (DAMPs) that contribute to inflammation and trigger DD have not been well characterized. Extracellular high mobility group box-1 (HMGB1) protein has been implicated as a potent DAMP and pro-inflammatory stimulus in the immune system. In this study, we show that HMGB1 and IL-6 levels increase in patients with advanced DD in comparison to early DD. This study further tested the hypothesis that HMGB1 promotes inflammatory signaling driving DD in human nucleus pulposus (NP) cells and tissue. Immunofluorescence and western blot analysis confirmed the expression of HMGB1 and its extracellular release by NP cells under cell stress. Gene expression and protein quantification indicate that HMGB1 stimulates the expression IL-6 and MMP-1 in a dose-dependent manner. The contributions of toll-like receptor (TLR) −2, −4 and receptor for advanced glycation end products (RAGE) as receptors mediating HMGB1 signaling was examined using small molecule inhibitors. Inhibition of TLR-4 signaling, with TAK-242, completely abrogated HMGB1 induced IL-6 and MMP-1 expression, whereas inhibition of TLR-2, with O-vanillin, or RAGE, with FPS-ZM1, had mild inhibitory effects. HMGB1 stimulation activated NF-κB signaling while TAK-242 cotreatment abrogated it. Lastly, effects of HMGB1 on matrix deposition was evaluated in a 3D culture system of human NP cells. These results implicate HMGB1 as a potent DAMP that promotes inflammation in NP cells and degradation of NP tissues. TLR4-HMGB1 axis is a potential major pathway to alleviate disc inflammation and mitigate DD.
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影响因子：
5.7
作者：
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通讯作者：
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影响因子：
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