Zaal Anouk, Dieker Miranda, Oudenampsen Manon, Turksma Annelies W, Lissenberg-Thunnissen Suzanne N, Wouters Diana, van Ham S Marieke, Ten Brinke Anja
Department of Immunopathology, Sanquin Research, Amsterdam, Netherlands.
Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2017 Jul 14;8:818. doi: 10.3389/fimmu.2017.00818. eCollection 2017.
Activation of antigen-presenting dendritic cells (DCs) and the complement system are essential early events in the immune defense against invading pathogens. Recently, we and others demonstrated immunological crosstalk between signaling from receptors recognizing complement activation products and PAMPs on DCs. This affects DC effector function, as demonstrated by the finding that C5a prevents induction of pro-inflammatory cytokines by toll-like receptor (TLR) ligands in human monocyte-derived DCs (moDCs). Here, we demonstrate that this regulatory crosstalk is specifically important in 6-sulfo LacNAc dendritic cells (slanDCs), the most pro-inflammatory DC subset found in human. C5aR and TLR signaling show profound interference in the ERK/p38/CREB1 signaling pathways. C5aR signaling accelerates TLR-induced CREB1 phosphorylation both in moDC and slanDC. This is key in the regulatory effect of C5a on pro-inflammatory DC maturation by mediating induction of IL-10, which subsequently inhibits pro-inflammatory cytokine production negative feedback signaling. Importantly, the regulatory effect of C5a affects T-cell immunity by decreasing Th1 and cytotoxic CD8 T-cell responses. The finding that the pro-inflammatory effector function of slanDC can be down modulated by activation products of the complement system highlights the existence of intricate regulatory interactions between various arms of the immune system. Intensive immune monitoring of patients suffering from complement-mediated diseases or patients receiving complement modulating compounds can give more inside in the contribution of complement receptor and TLR crosstalk in APCs in disease.
抗原呈递树突状细胞（DCs）的激活和补体系统是免疫防御入侵病原体的重要早期事件。最近，我们和其他人证明了识别补体激活产物的受体信号与DCs上的病原体相关分子模式（PAMPs）之间存在免疫串扰。这会影响DC效应功能，如在人单核细胞衍生的DCs（moDCs）中发现C5a可阻止Toll样受体（TLR）配体诱导促炎细胞因子。在此，我们证明这种调节性串扰在6-磺基乳糖胺树突状细胞（slanDCs）中尤为重要，slanDCs是人类中发现的最具促炎作用的DC亚群。C5aR和TLR信号在ERK/p38/CREB1信号通路中表现出深刻的干扰。C5aR信号在moDC和slanDC中均加速TLR诱导的CREB1磷酸化。这是C5a对促炎DC成熟发挥调节作用的关键，通过介导IL-10的诱导，随后抑制促炎细胞因子产生负反馈信号。重要的是，C5a的调节作用通过降低Th1和细胞毒性CD8 T细胞反应来影响T细胞免疫。补体系统激活产物可下调slanDC的促炎效应功能这一发现突出了免疫系统各分支之间存在复杂的调节相互作用。对患有补体介导疾病的患者或接受补体调节化合物的患者进行密集免疫监测，可以更深入了解补体受体和TLR串扰在疾病中对APC的贡献。
