Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium
Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium
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DOI：
10.1073/pnas.1620664114
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发表时间：
2017-07-25
影响因子：
11.1
通讯作者：
Lane, Andrew P.
中科院分区：
文献类型：
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作者：
Chen, Mengfei;Reed, Randall R.;Lane, Andrew P.
位于嗅上皮基底层的成体神经干细胞/祖细胞即使在严重损伤后也能够重建神经上皮。这种再生能力背后的分子事件仍然难以捉摸。在这里，我们表明，神经上皮损伤后的修复是伴随着一个急性的，但自限性，炎症过程。地塞米松减弱炎性细胞募集和细胞因子产生损害祖细胞水平基底细胞（HBC）的增殖和随后的神经元分化。使用TNF-α受体缺陷小鼠，我们确定TNF-α信号传导是这种炎症和修复过程的重要贡献者，主要通过TNF-α受体1。HBC选择性基因切除RelA（p65），NF-κ B通路的转录激活因子，在再生的早期阶段延缓炎症并阻碍增殖，并表明HBC直接参与免疫应答和神经发生之间的相互作用。再生神经上皮中RelA的缺失扰乱了增殖和凋亡之间的稳态，同时增强了JNK信号传导。总之，我们的研究结果支持一种模型，其中损伤后的急性炎症部分通过NF-κ B介导的信号传导启动重要的再生信号，激活神经干细胞重建嗅上皮。
Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-alpha receptor-deficient mice, we identify TNF-alpha signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-alpha receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-kappa B pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-kappa B-mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.