HSP90 Inhibitor 17-AAG Attenuates Nucleus Pulposus Inflammation and Catabolism Induced by M1-Polarized Macrophages.
HSP90 Inhibitor 17-AAG Attenuates Nucleus Pulposus Inflammation and Catabolism Induced by M1-Polarized Macrophages.
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DOI：
10.3389/fcell.2021.796974
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发表时间：
2021
影响因子：
5.5
通讯作者：
Shao Z
中科院分区：
文献类型：
--
作者：
Zhang S;Wang P;Hu B;Liu W;Lv X;Chen S;Shao Z
促炎巨噬细胞诱导的过度激活炎症和分解代谢参与了椎间盘退变（IVDD）的病理过程。我们的前期研究提示了抑制热休克蛋白90 （HSP90）对IVDD的保护作用，但其机制有待进一步研究。本研究探讨了HSP90抑制剂17-AAG对m1极化巨噬细胞诱导的髓核（NP）炎症和分解代谢的影响。免疫组化染色显示，人IVD退行性组织中巨噬细胞大量浸润，尤其是M1表型，白细胞介素(IL)-1β、肿瘤坏死因子(TNF)-α、基质金属蛋白酶（MMP）13水平升高。炎症NP细胞（NPCs）的条件培养基（CM）增强了巨噬细胞的M1极化，M1巨噬细胞的条件培养基（CM）促进了NPCs中炎症因子和基质蛋白酶的表达，而M2巨噬细胞的条件培养基（CM）没有促进炎症因子和基质蛋白酶的表达。此外，我们发现17-AAG可以通过调节巨噬细胞和npc来表现抗炎和抗分解代谢作用。一方面，17-AAG通过抑制核因子-κB （NF-κB）通路和丝裂原活化蛋白激酶（MAPK）通路减弱M1巨噬细胞的促炎活性。另一方面，17-AAG通过上调HSP70和抑制Janus kinase 2 (JAK2)-信号传导和转录激活因子3 （STAT3）通路，抑制m1 - cm诱导的npc炎症和分解代谢。此外，体外IVD培养模型和小鼠椎间盘穿刺模型均支持17-AAG处理降低IVD组织中炎症因子和基质蛋白酶水平。综上所述，HSP90抑制剂17-AAG可减轻M1巨噬细胞诱导的NP炎症和分解代谢，提示17-AAG是治疗IVDD的有希望的候选药物。
Overactivated inflammation and catabolism induced by proinflammatory macrophages are involved in the pathological processes of intervertebral disc (IVD) degeneration (IVDD). Our previous study suggested the protective role of inhibiting heat shock protein 90 (HSP90) in IVDD, while the underlying mechanisms need advanced research. The current study investigated the effects of HSP90 inhibitor 17-AAG on nucleus pulposus (NP) inflammation and catabolism induced by M1-polarized macrophages. Immunohistochemical staining of degenerated human IVD samples showed massive infiltration of macrophages, especially M1 phenotype, as well as elevated levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)13. The conditioned medium (CM) of inflamed NP cells (NPCs) enhanced M1 polarization of macrophages, while the CM of M1 macrophages but not M2 macrophages promoted the expression of inflammatory factors and matrix proteases in NPCs. Additionally, we found that 17-AAG could represent anti-inflammatory and anti-catabolic effects by modulating both macrophages and NPCs. On the one hand, 17-AAG attenuated the pro-inflammatory activity of M1 macrophages via inhibiting nuclear factor-κB (NF-κB) pathway and mitogen-activated protein kinase (MAPK) pathways. On the other hand, 17-AAG dampened M1-CM-induced inflammation and catabolism in NPCs by upregulating HSP70 and suppressing the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, both in vitro IVD culture models and murine disc puncture models supported that 17-AAG treatment decreased the levels of inflammatory factors and matrix proteases in IVD tissues. In conclusion, HSP90 inhibitor 17-AAG attenuates NP inflammation and catabolism induced by M1 macrophages, suggesting 17-AAG as a promising candidate for IVDD treatment.
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影响因子：
3
作者：
Kobayashi, Shigeru;Meir, Adam;Baba, Hisatoshi
通讯作者：
Baba, Hisatoshi
影响因子：
15.9
作者：
Marubayashi, Sachie;Koppikar, Priya;Levine, Ross L.
通讯作者：
Levine, Ross L.
痛苦的椎间盘退变和炎症：从实验室证据到临床干预
影响因子：
12.7
作者：
Lyu FJ;Cui H;Pan H;Mc Cheung K;Cao X;Iatridis JC;Zheng Z
通讯作者：
Zheng Z
DOI：
10.1038/nri3073
发表时间：
2011-10-14
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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DOI：
10.1038/nrrheum.2013.160
发表时间：
2014-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
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