Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, 241000, China.
Immunol Cell Biol. 2018 Oct;96(9):912-921. doi: 10.1111/imcb.12051. Epub 2018 Apr 19.
As professional antigen-presenting cells, dendritic cells (DCs) initiate and regulate immune responses against inflammation. The invasion of pathogens into the body, however, can in turn cause the change of DCs in both activity and viability, which ultimately affect immune homeostasis. The exact mechanisms that the bacteria utilize to alter the lifespan of DCs, however, are far from clear. In this study, we found that the bacterial wall compound lipopolysaccharide (LPS) can promote the survival of GM-CSF-differentiated DCs (GM-DCs). At molecular levels, we demonstrated that GM-DCs had distinct pattern of mRNA expression for anti-apoptotic BCL-2 family members, of which, Bcl-x increased significantly following LPS stimulation. Interestingly, specific inhibition of BCL-XL protein alone was sufficient to remove the anti-apoptotic effects of LPS on BM-DCs. Further study of the signaling mechanisms revealed that although LPS can activate both Erk MAP kinase and PI3 kinase pathways, only blocking of PI3K abolished both Bcl-x upregulation and the enhanced survival phenotype, suggesting that the PI3K signaling mediated the upregulation of Bcl-x for the LPS-induced pro-survival in GM-DCs. Collectively, this study unveils a molecular mechanism that DCs adapt to maintain innate immunity against the invasion of pathogens.
作为专业的抗原呈递细胞，树突状细胞（DCs）启动并调节针对炎症的免疫反应。然而，病原体侵入体内会反过来导致 DCs 的活性和存活能力发生变化，从而最终影响免疫稳态。但是，细菌利用的确切机制来改变 DCs 的寿命还远不清楚。在这项研究中，我们发现细菌细胞壁化合物脂多糖（LPS）可以促进 GM-CSF 分化的 DCs（GM-DCs）的存活。在分子水平上，我们证明 GM-DCs 对凋亡抑制 BCL-2 家族成员的 mRNA 表达具有明显的模式，其中 LPS 刺激后 Bcl-x 显著增加。有趣的是，单独特异性抑制 BCL-XL 蛋白就足以消除 LPS 对 BM-DCs 的抗凋亡作用。对信号机制的进一步研究表明，尽管 LPS 可以激活 Erk MAP 激酶和 PI3 激酶途径，但仅阻断 PI3K 就可以消除 Bcl-x 的上调和增强的存活表型，表明 PI3K 信号转导介导了 LPS 诱导的 GM-DCs 中 Bcl-x 的上调，以促进生存。总之，这项研究揭示了 DCs 适应以维持针对病原体入侵的固有免疫的分子机制。
