Barrientos Lorena, Bignon Alexandre, Gueguen Claire, de Chaisemartin Luc, Gorges Roseline, Sandré Catherine, Mascarell Laurent, Balabanian Karl, Kerdine-Römer Saadia, Pallardy Marc, Marin-Esteban Viviana, Chollet-Martin Sylvie
INSERM, Unité Mixte de Recherche-S 996, "Cytokines, chimiokines et immunopathologie," Université Paris-Sud, 92296 Châtenay-Malabry and Clamart, France; Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France;
INSERM, Unité Mixte de Recherche-S 996, "Cytokines, chimiokines et immunopathologie," Université Paris-Sud, 92296 Châtenay-Malabry and Clamart, France; Laboratory of Excellence in Research on Medication and Innovative Therapeutics, 92296 Clamart, France;
J Immunol. 2014 Dec 1;193(11):5689-98. doi: 10.4049/jimmunol.1400586. Epub 2014 Oct 22.
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-α, 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-γ 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.
多形核中性粒细胞（PMN）在炎症中起核心作用，并参与炎症的控制，特别是通过可溶性介质或细胞间接触调节树突状细胞（DC）的功能。在这种情况下，PMN释放的中性粒细胞胞外陷阱（NETs）可能发挥作用。为了评估NETs对DC成熟的影响，我们建立了一个基于单核细胞衍生DC（moDC）的模型，并校准了从新鲜人PMN中分离的NETs。我们发现单独分离的NETs对moDC没有明显影响。相反，它们下调了LPS诱导的moDC成熟，表现为HLA-DR、CD80、CD83和CD86的表面表达降低，以及细胞因子产生下调（TNF-α、IL-6、IL-12、IL-23），而耐受性DC基因的表达没有增加。此外，在moDC成熟过程中存在NETs会降低这些moDC在自体和异体条件下诱导T淋巴细胞增殖的能力，并通过促进Th2细胞因子（IL-5和IL-13）的产生和减少Th1和Th17细胞因子（IFN-γ和IL-17）的产生来调节CD4(+) T淋巴细胞极化。有趣的是，当moDC在NETs存在下成熟时，其淋巴趋化因子受体CCR7和CXCR4的表达和活性没有改变。总之，这些发现揭示了NETs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。
