Regulatory NLRs Control the RLR-Mediated Type I Interferon and Inflammatory Responses in Human Dendritic Cells.
Regulatory NLRs Control the RLR-Mediated Type I Interferon and Inflammatory Responses in Human Dendritic Cells.
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DOI：
10.3389/fimmu.2018.02314
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发表时间：
2018
影响因子：
7.3
通讯作者：
Pazmandi K
中科院分区：
文献类型：
--
作者：
Fekete T;Bencze D;Szabo A;Csoma E;Biro T;Bacsi A;Pazmandi K
已发现核苷酸结合域富亮氨酸重复序列（NLR）家族的独特成员调节由模式识别受体（PRR）的其它家族如Toll样受体（TLR）和视黄酸诱导基因I（RIG-I）样受体（RLR）启动的细胞内信号传导途径。浆细胞样树突状细胞（pDC）是最强的I型干扰素（IFN）产生细胞，其优先利用内体TLR来引发抗病毒IFN应答。相比之下，常规DC（cDC）主要使用在其中组成型表达的胞质TLR来感测外源核酸。以前，我们已经报道，虽然RIG-I是缺乏休息的pDC，它是诱导TLR刺激。在最近的研究中，我们研究了NLR的调节能力，即NLRC 5和NLRX 1直接与显示不同RLR表达的DC亚型中的TLR介导的信号通路相关，特别是在pDC和单核细胞衍生的DC（moDC）中。在这里，我们证明，类似于RLRs，NLRC 5也是诱导后TLR 9刺激，而NLRX 1组成型表达的pDC。抑制pDC中的NLRC 5和NLRX 1表达增强了TLR刺激的I型IFN的表达，但不影响促炎细胞因子TNF、IL-6和趋化因子IL-8的产生。此外，我们表明，未成熟的moDC不断表达在其分化过程中逐渐上调的RLR、NLRX 1和NLRC 5。与pDC类似，NLRX 1抑制增加了moDC中TLR诱导的I型IFN的产生。有趣的是，NLRX 1沉默的moDC的RLR刺激导致促炎细胞因子产生和IκBα降解的显著增加，表明NF-κB活性增加。相反，NLRC 5似乎对moDC中TLR介导的细胞因子应答没有任何影响。总之，我们的结果表明，NLRX 1负调控TLR介导的I型IFN的生产在pDC和moDC。此外，我们表明，NLRX 1抑制促炎细胞因子分泌的moDC，但不在pDC后RLR刺激。有趣的是，NLRC 5抑制pDC中TLR诱导的I型IFN分泌，但似乎对moDC中的RLR途径没有任何调节功能。总的来说，我们的工作表明，TLR介导的先天性免疫反应主要是由NLRX 1和NLRC 5在人DC中的部分控制。
Unique members of the nucleotide-binding domain leucine-rich repeat (NLR) family have been found to regulate intracellular signaling pathways initiated by other families of pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) and retinoic-acid inducible gene I (RIG-I)-like receptors (RLRs). Plasmacytoid dendritic cells (pDCs), the most powerful type I interferon (IFN) producing cells, preferentially employ endosomal TLRs to elicit antiviral IFN responses. By contrast, conventional DCs (cDCs) predominantly use cytosolic RLRs, which are constitutively expressed in them, to sense foreign nucleic acids. Previously we have reported that, though RIG-I is absent from resting pDCs, it is inducible upon TLR stimulation. In the recent study we investigated the regulatory ability of NLRs, namely NLRC5 and NLRX1 directly associated with the RLR-mediated signaling pathway in DC subtypes showing different RLR expression, particularly in pDCs, and monocyte-derived DCs (moDCs). Here we demonstrate that similarly to RLRs, NLRC5 is also inducible upon TLR9 stimulation, whereas NLRX1 is constitutively expressed in pDCs. Inhibition of NLRC5 and NLRX1 expression in pDCs augmented the RLR-stimulated expression of type I IFNs but did not affect the production of the pro-inflammatory cytokines TNF, IL-6, and the chemokine IL-8. Further we show that immature moDCs constantly express RLRs, NLRX1 and NLRC5 that are gradually upregulated during their differentiation. Similarly to pDCs, NLRX1 suppression increased the RLR-induced production of type I IFNs in moDCs. Interestingly, RLR stimulation of NLRX1-silenced moDCs leads to a significant increase in pro-inflammatory cytokine production and IκBα degradation, suggesting increased NF-κB activity. On the contrary, NLRC5 does not seem to have any effect on the RLR-mediated cytokine responses in moDCs. In summary, our results indicate that NLRX1 negatively regulates the RLR-mediated type I IFN production both in pDCs and moDCs. Further we show that NLRX1 inhibits pro-inflammatory cytokine secretion in moDCs but not in pDCs following RLR stimulation. Interestingly, NLRC5 suppresses the RLR-induced type I IFN secretion in pDCs but does not appear to have any regulatory function on the RLR pathway in moDCs. Collectively, our work demonstrates that RLR-mediated innate immune responses are primarily regulated by NLRX1 and partly controlled by NLRC5 in human DCs.
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