HDAC3 inhibition ameliorates spinal cord injury by immunomodulation.
HDAC3 inhibition ameliorates spinal cord injury by immunomodulation.
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DOI：
10.1038/s41598-017-08535-4
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发表时间：
2017-08-17
影响因子：
4.6
通讯作者：
Zou H
中科院分区：
文献类型：
--
作者：
Kuboyama T;Wahane S;Huang Y;Zhou X;Wong JK;Koemeter-Cox A;Martini M;Friedel RH;Zou H
脊髓损伤 (SCI) 后，小胶质细胞和浸润巨噬细胞的先天免疫反应会清除细胞碎片并促进组织修复，但也会因炎症反应造成继发性损伤。免疫调节旨在最大化先天免疫的有益作用，同时最小化其有害作用，可能有助于 SCI 后的功能恢复。然而，人们对先天免疫细胞中炎症基因网络全局重编程的细胞内驱动因素知之甚少。在这里，我们发现 SCI 导致损伤部位先天免疫细胞中组蛋白脱乙酰酶 3 (HDAC3) 的上调。值得注意的是，用选择性小分子抑制剂阻断 HDAC3 可将小胶质细胞/巨噬细胞的反应转向炎症抑制，从而产生神经保护表型并改善 SCI 模型的功能恢复。从机制上讲，HDAC3 活性在很大程度上负责组蛋白脱乙酰化和原代小胶质细胞对经典炎症刺激的炎症反应。我们的研究结果揭示了 HDAC3 抑制剂通过抑制炎症细胞因子促进 SCI 后功能恢复的新功能，从而为 SCI 修复的免疫调节指明了新方向。
Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
3.7
作者：
Morganti JM;Riparip LK;Rosi S
通讯作者：
Rosi S
影响因子：
64.8
作者：
Alenghat, Theresa;Osborne, Lisa C.;Saenz, Steven A.;Kobuley, Dmytro;Ziegler, Carly G. K.;Mullican, Shannon E.;Choi, Inchan;Grunberg, Stephanie;Sinha, Rohini;Wynosky-Dolfi, Meghan;Snyder, Annelise;Giacomin, Paul R.;Joyce, Karen L.;Hoang, Tram B.;Bewtra, Meenakshi;Brodsky, Igor E.;Sonnenberg, Gregory F.;Bushman, Frederic D.;Won, Kyoung-Jae;Lazar, Mitchell A.;Artis, David
通讯作者：
Artis, David
DOI：
10.1101/lm.036699.114
发表时间：
2015-04
期刊：
Learning & memory (Cold Spring Harbor, N.Y.)
影响因子：
--
作者：
Bowers ME;Xia B;Carreiro S;Ressler KJ
通讯作者：
Ressler KJ
影响因子：
6.2
作者：
Hines, Dustin J.;Hines, Rochelle M.;Macvicar, Brian A.
通讯作者：
Macvicar, Brian A.