IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier.
IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier.
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DOI：
10.1186/s13024-016-0116-1
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发表时间：
2016-07-22
影响因子：
15.1
通讯作者：
Cho IH
中科院分区：
文献类型：
--
作者：
Lee MJ;Bing SJ;Choi J;Jang M;Lee G;Lee H;Chang BS;Jee Y;Lee SJ;Cho IH
炎性髓系细胞活化是实验性自身免疫性脑脊髓炎（EAE）的标志之一，然而炎性髓系细胞活化在EAE中的体内作用尚未明确解决。众所周知，IKK/NF-κB是调节炎性骨髓活化的关键信号通路。我们使用髓系细胞类型特异性ikkβ基因条件性敲除小鼠（LysM-Cre/IkkβF/F）研究了炎性髓系细胞活化在髓鞘少突胶质细胞糖蛋白（MOG）肽诱导的EAE中的体内作用。在我们的研究中，与野生型小鼠（WT，Ikk β F/F）相比，LysM-Cre/Ikk β F/F小鼠缓解了EAE的临床体征，相应于脊髓脱髓鞘、小胶质细胞活化和脊髓中免疫细胞浸润的减少。髓样ikkβ基因缺失显著降低了脊髓和淋巴结中CD 4 +/IFN-γ+（Th 1）和CD 4 +/IL-17+（Th 17）细胞的百分比，但增加了CD 4 +/CD 25 +/Foxp 3+（Treg）细胞的百分比，这与LysM-Cre/IkkβF/F EAE小鼠脊髓中IFN-γ、IL-17、IL-23和Foxp 3的mRNA表达改变相对应。此外，髓样IKKβ缺失在EAE中的有益作用与血脑屏障（BBB）通透性降低相对应。我们的研究结果强烈提示IKK/NF-kB诱导的髓系细胞活化通过激活Th 1和Th 17应答并损害BBB而加重EAE。通过特异性靶向骨髓细胞中的IKKβ而开发高效的NF-κB抑制剂可能对MS和其他自身免疫性疾病具有治疗潜力。本文的在线版本（doi：10.1186/s13024-016-0116-1）包含补充材料，可供授权用户使用。
The inflammatory myeloid cell activation is one of the hallmarks of experimental autoimmune encephalomyelitis (EAE), yet the in vivo role of the inflammatory myeloid cell activation in EAE has not been clearly resolved. It is well-known that IKK/NF-κB is a key signaling pathway that regulates inflammatory myeloid activation. We investigated the in vivo role of inflammatory myeloid cell activation in myelin oligodendrocyte glycoprotein (MOG) peptides-induced EAE using myeloid cell type-specific ikkβ gene conditional knockout-mice (LysM-Cre/IkkβF/F). In our study, LysM-Cre/IkkβF/F mice had alleviated clinical signs of EAE corresponding to the decreased spinal demyelination, microglial activation, and immune cell infiltration in the spinal cord, compared to the wild-type mice (WT, IkkβF/F). Myeloid ikkβ gene deletion significantly reduced the percentage of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells but increased the percentages of CD4+/CD25+/Foxp3+ (Treg) cells in the spinal cord and lymph nodes, corresponding to the altered mRNA expression of IFN-γ, IL-17, IL-23, and Foxp3 in the spinal cords of LysM-Cre/IkkβF/F EAE mice. Also, the beneficial effect of myeloid IKKβ deletion in EAE corresponded to the decreased permeability of the blood brain barrier (BBB). Our findings strongly suggest that IKK/NF-kB-induced myeloid cell activation exacerbates EAE by activating Th1 and Th17 responses and compromising the BBB. The development of NF-κB inhibitory agents with high efficacy through specific targeting of IKKβ in myeloid cells might be of therapeutic potential in MS and other autoimmune disorders. The online version of this article (doi:10.1186/s13024-016-0116-1) contains supplementary material, which is available to authorized users.