Impact of Notch1 Deletion in Macrophages on Proinflammatory Cytokine Production and the Outcome of Experimental Autoimmune Encephalomyelitis.
Impact of Notch1 Deletion in Macrophages on Proinflammatory Cytokine Production and the Outcome of Experimental Autoimmune Encephalomyelitis.
复制标题
DOI：
10.4049/jimmunol.1401770
复制
发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Palaga T
中科院分区：
文献类型：
--
作者：
Wongchana W;Lawlor RG;Osborne BA;Palaga T
Notch信号转导参与调节活化的巨噬细胞中TLR介导的应答。在这项研究中，我们研究了Notch信号在实验性自身免疫性脑脊髓炎（EAE）模型中的巨噬细胞中的影响。为了检查Notch信号传导缺陷在EAE中活化巨噬细胞中的影响，在诱导EAE之前进行源自Notch 1fl/fl X Mx 1cre +/-（N1 KO）或CSL/Rbp-jkfl/fl X Mx 1cre +/-（CSL/RbP-Jκ KO）小鼠的活化巨噬细胞的过继转移。与接受野生型或CSL/RBP-Jκ KO巨噬细胞的小鼠相比，接受活化的N1 KO巨噬细胞的小鼠显示EAE严重程度降低。来自这些小鼠的MOG 35 -55肽对脾细胞的体外再刺激显示，与对照小鼠相比，来自接受N1 KO巨噬细胞的小鼠的细胞产生显著更少的IL-17，而IFNγ产生在两组中相似。我们发现，与野生型相比，活化的N1 KO（而不是CSL/RBP-Jκ KO）巨噬细胞产生的IL-6较少，CD 80表达较低，并且在IL-12 p40/70产生方面没有表现出任何缺陷，而来自CSL/RBP-Jκ KO小鼠的活化巨噬细胞表型γ分泌酶抑制剂（GSI）治疗可减少IL-12 p40/70的产生。此外，NF-κB亚基c-Rel的核转位在GSI处理的和CSL/RBP-Jκ KO的巨噬细胞中受到损害，但在N1 KO的巨噬细胞中没有。这些结果表明，Notch 1和CSL/RBP-Jκ在巨噬细胞可能会影响EAE的严重程度不同，可能通过调节IL-6和CD 80的表达，这参与了Th 17，而不是Th 1的反应。
Notch signaling is involved in regulating TLR-mediated responses in activated macrophages. In this study, we investigated the impact of Notch signaling in macrophages in an experimental autoimmune encephalomyelitis (EAE) model. To examine the impact of deficiency in Notch signaling in activated macrophages in EAE, an adoptive transfer of activated macrophages derived from Notch1fl/fl X Mx1cre+/− (N1KO) or CSL/Rbp-jkfl/fl X Mx1cre+/− (CSL/RBP-Jκ KO) mice was performed prior to induction of EAE. Mice receiving activated N1KO macrophages showed decreased severity of EAE, compared with mice receiving wild type or CSL/RBP-Jκ KO macrophages. In vitro re-stimulation of splenocytes by MOG35-55 peptide from these mice revealed that cells from mice receiving N1KO macrophages produced significantly less IL-17 compared with the control mice, whereas IFNγ production was similar in both groups. We found that activated N1KO, but not CSL/RBP-Jκ KO, macrophages produced less IL-6 and had lower CD80 expression, compared with wild type and did not exhibit any defect in IL-12p40/70 production, whereas activated macrophages from CSL/RBP-Jκ KO mice phenocopied gamma secretase inhibitor (GSI) treatment for reduced IL-12p40/70 production. Furthermore, the nuclear translocation of the NF-κB subunit c-Rel was compromised in GSI-treated and CSL/RBP-Jκ KO but not N1KO macrophages. These results suggest that Notch1 and CSL/RBP-Jκ in macrophages may affect the severity of EAE differently, possibly through modulating IL-6 and CD80 expression, which is involved in the Th17 but not Th1 response.