Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes
Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes
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DOI：
10.1016/j.molimm.2019.03.003
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发表时间：
2019-07-01
影响因子：
3.6
通讯作者：
Pastelin-Palacios, Rodolfo
中科院分区：
文献类型：
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作者：
Aldapa-Vega, Gustavo;Adan Moreno-Eutimio, Mario;Pastelin-Palacios, Rodolfo
鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌（Typhimurium）改变其脂多糖（LPS）的结构以响应环境。在S.鼠伤寒沙门氏菌对应于具有七酰化脂质A的LPS（LPS 430）和在其脂质A上具有修饰的磷酸基团的LPS（LPS 435）。我们先前已经表明，这些修饰的LPS具有比野生型（WT）LPS更低的诱导小鼠中促炎细胞因子产生的能力。然而，尚不清楚LPS 430和LPS 435是否也可以破坏人类细胞中的先天免疫应答。在本研究中，我们发现LPS 430和LPS 435诱导人单核细胞产生促炎细胞因子的效率低于WT LPS，此外，我们发现TLR 4/MD-2复合物响应LPS 430的二聚化减少，这表明结构修饰的LPS与WT LPS相比被该受体不同地感受;然而，LPS 430和435诱导的转录因子NF-κ B p65、IRF 3、p38和ERK 1/2的活化与WT LPS相似。LPS 430-和LPS 435-活化的单核细胞的微阵列分析揭示了与WT LPS诱导的谱相比仅在microRNA基因的表达水平上具有差异的基因转录谱，表明LPS 430和LPS 435中存在的脂质A修饰对人TLR 4/MD-2复合物的活化具有中等影响。我们的研究结果与了解LPS对免疫反应的调节有关，这些知识可能有助于开发新型佐剂和免疫调节剂。
Salmonella enterica serovar Typhimurium (S. Typhimurium) changes the structure of its lipopolysaccharide (LPS) in response to the environment. The two main LPS variants found in S. Typhimurium correspond to LPS with a hepta-acylated lipid A (LPS 430) and LPS with modified phosphate groups on its lipid A (LPS 435). We have previously shown that these modified LPS have a lower capacity than wild type (WT) LPS to induce the production of pro-inflammatory cytokines in mice. Nevertheless, it is not know if LPS 430 and LPS 435 could also subvert the innate immune responses in human cells. In this study, we found that LPS 430 and LPS 435 were less efficient than WT LPS to induce the production of pro-inflammatory cytokines by human monocytes, in addition we found a decreased dimerization of the TLR4/MD-2 complex in response to LPS 430, suggesting that structurally modified LPS are sensed differently than WT LPS by this receptor; however, LPS 430 and 435 induced similar activation of the transcription factors NF-kappa B p65, IRF3, p38 and ERK1/2 than WT LPS. Microarray analysis of LPS 430- and LPS 435-activated monocytes revealed a gene transcription profile with differences only in the expression levels of microRNA genes compared to the profile induced by WT LPS, suggesting that the lipid A modifications present in LPS 430 and LPS 435 have a moderate effect on the activation of the human TLR4/MD-2 complex. Our results are relevant to understand LPS modulation of immune responses and this knowledge could be useful for the development of novel adjuvants and immunomodulators.