Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling.
Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling.
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DOI：
10.1155/2021/6426225
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Chen X;Yao N;Lin Z;Wang Y
慢性脑低灌注可导致脑白色物质缺血性损伤和认知功能障碍，其机制尚不清楚。免疫蛋白酶体与急性缺血性中风和多发性硬化的发病机制有关。然而，免疫蛋白酶体在慢性脑低灌注脑组织中的表达及其作用尚不清楚。 采用双侧颈动脉狭窄（BCAS）建立慢性白色脑缺血损伤小鼠模型。将选择性免疫蛋白酶体亚单位低分子量肽-7（LMP 7）抑制剂PR 957给予小鼠。在BCAS后评估认知功能、白色物质完整性和潜在通路。 本研究发现，BCAS后慢性脑灌注不足诱导脑白色物质脱髓鞘和认知障碍，伴随免疫蛋白酶体LMP 2和LMP 7表达升高，星形胶质细胞和小胶质细胞活化，以及炎性细胞因子（例如，白细胞介素-1 β（IL-1β）、肿瘤坏死因子-α（TNF-α）、IL-10、转化生长因子-β1（TGFβ1）和胰岛素样生长因子-1（IGF-1））。然而，用特异性蛋白酶体抑制剂PR 957抑制LMP 7显著减轻了白色物质的组织学损伤，抑制了炎症反应，并通过改善认知功能而减轻。PR 957还能显著上调TGFβ1、Smad 2/3的总表达和磷酸化水平，促进脑髓鞘再生。令人惊讶的是，PR 957单独对假手术（BCAS未手术）小鼠中的神经炎症反应和TGFβ/Smad信号传导的活化没有影响。 其机制可能与免疫蛋白酶体调节TGFβ/Smad信号介导的神经炎症和少突胶质细胞髓鞘再生有关。
Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.
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影响因子：
3.1
作者：
Angeles, Arkhjamil;Fung, Gabriel;Luo, Honglin
通讯作者：
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影响因子：
15.1
作者：
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影响因子：
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作者：
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影响因子：
4.4
作者：
Kremer, Marcel;Henn, Anja;Groettrup, Marcus
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Groettrup, Marcus
影响因子：
3.4
作者：
De Boeck M;ten Dijke P
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ten Dijke P