Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells
Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells
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DOI：
10.4049/jimmunol.1400586
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发表时间：
2014-12-01
影响因子：
4.4
通讯作者：
Chollet-Martin, Sylvie
中科院分区：
文献类型：
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作者：
Barrientos, Lorena;Bignon, Alexandre;Chollet-Martin, Sylvie
中性粒细胞（PMN）在炎症中起着重要作用，并参与其控制，特别是通过可溶性介质或细胞-细胞接触调节树突状细胞（DC）的功能。中性粒细胞释放的神经元细胞外陷阱（NETs）可能在此过程中发挥作用。为了评估NET对DC成熟的影响，我们开发了一个基于单核细胞衍生DC（moDC）和从新鲜人PMN分离的校准NET的模型。我们发现单独的NET对moDC没有明显的影响。相反，它们下调LPS诱导的moDC成熟，如HLA-DR、CD 80、CD 83和CD 86的表面表达降低以及细胞因子产生（TNF-α、IL-6、IL-12、IL-23）下调所示，而致耐受性DC基因的表达没有增加。此外，在moDC成熟过程中NET的存在降低了这些moDC在自体和同种异体条件下诱导T淋巴细胞增殖的能力，并通过促进Th 2细胞因子（IL-5和IL-13）的产生和减少Th 1和Th 17细胞因子（IFN-γ和IL-17）的产生来调节CD 4（+）T淋巴细胞极化。有趣的是，在NET存在下，当moDC成熟时，moDC上淋巴样趋化因子受体CCR 7和CXCR 4的表达和活性没有改变。总之，这些发现揭示了NET在适应性免疫反应中的新作用，调节一些moDC功能，从而参与炎症的控制。
Polymorphonuclear neutrophils (PMN) play a central role in inflammation and participate in its control, notably by modulating dendritic cell (DC) functions via soluble mediators or cell-cell contacts. Neutrophil extracellular traps (NETs) released by PMN could play a role in this context. To evaluate NET effects on DC maturation, we developed a model based on monocyte-derived DC (moDC) and calibrated NETs isolated from fresh human PMN. We found that isolated NETs alone had no discernable effect on moDC. In contrast, they downregulated LPS-induced moDC maturation, as shown by decreased surface expression of HLA-DR, CD80, CD83, and CD86, and by downregulated cytokine production (TNF-alpha, IL-6, IL-12, IL-23), with no increase in the expression of tolerogenic DC genes. Moreover, the presence of NETs during moDC maturation diminished the capacity of these moDC to induce T lymphocyte proliferation in both autologous and allogeneic conditions, and modulated CD4(+) T lymphocyte polarization by promoting the production of Th2 cytokines (IL-5 and IL-13) and reducing that of Th1 and Th17 cytokines (IFN-gamma and IL-17). Interestingly, the expression and activities of the lymphoid chemokine receptors CCR7 and CXCR4 on moDC were not altered when moDC matured in the presence of NETs. Together, these findings reveal a new role for NETs in adaptive immune responses, modulating some moDC functions and thereby participating in the control of inflammation.