cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.
cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.
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CREL和WNT5A/毛躁5受体介导的炎症调节揭示了新型神经保护素D1靶标的神经保护剂。
DOI：
10.1007/s10571-022-01231-6
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发表时间：
2023-04
影响因子：
4
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中科院分区：
文献类型：
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Wnt5A通过NFkB/P65在经历不补偿氧化应激(UOS)和实验性缺血性中风的视网膜色素上皮(RPE)细胞中触发炎症反应和损伤。我们发现Wnt5a-clathrin介导的摄取导致NFkB/p65的激活，并且Wnt5a以不依赖于外切体的方式分泌。我们发现二十二碳六烯酸(DHA)及其衍生物神经保护素D1(NPD1)上调c-rel的表达，结果是通过与Wnt5a启动子上的NFkB/p65竞争而钝化Wnt5a的丰度。Wnt5a增加了缺血性卒中半暗带和血液中的WNT5a，而DHA在伴随神经保护的同时降低了Wnt5a的丰度。Wnt5a结合的多肽抑制剂Box5也具有神经保护作用。DHA降低Wnt5a的表达与NFkB驱动的炎症细胞因子的表达下降是同步的，揭示了中风后的机制，就像暴露于UOS的RPE细胞一样。通过Box5限制Wnt5a的活性可以减少中风的大小，这表明神经保护与视网膜变性和中风后果的发生和发展有关。NPD1在两个位置干扰Wnt5a反馈环：(1)减少FZD5，从而使Wnt5a内化；(2)通过增强cREL活性，与p65/NFkB下游的内吞作用竞争。因此，Wnt5a的表达减少，其在RPE细胞和神经元中的炎症信号也减少。网上版载有补充材料，可在10.1007/s10571-022-01231-6查阅。
Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke. The online version contains supplementary material available at 10.1007/s10571-022-01231-6.
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影响因子：
4.1
作者：
Kurayoshi, Manabu;Yamamoto, Hideki;Kikuchi, Akira
通讯作者：
Kikuchi, Akira
影响因子：
4.6
作者：
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影响因子：
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作者：
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Schulte, Gunnar
DOI：
10.1073/pnas.0909409106
发表时间：
2009-11-17
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
3.1
作者：
Cisternas, Pedro;Salazar, Paulina;Inestrosa, Nibaldo C.
通讯作者：
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