Growth Factors, Cytokines, Cell Cycle Molecules Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity
Growth Factors, Cytokines, Cell Cycle Molecules Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity
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发表时间：
2009
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通讯作者：
F. Nichols;William J. Housley;Catherine A. O’Conor;Thomas Manning;Shuang Wu;R. Clark
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作者：
F. Nichols;William J. Housley;Catherine A. O’Conor;Thomas Manning;Shuang Wu;R. Clark
最近的报告表明，共生细菌可能在自身免疫性疾病中起到下调作用。在目前的研究中，我们证明了磷酸化二氢神经酰胺，一种来自常见的人类口腔细菌牙龈卟啉单胞菌和常见于胃肠道和其他器官的细菌的独特结构的脂类，能够增强自身免疫。我们之前已经报道过这些脂质对体外培养的人成纤维细胞具有促炎作用，在初步研究中，我们已经从手术切除的人颈动脉粥样硬化中恢复了这些脂类，这表明它们可能在人类炎症性疾病中发挥作用。为了研究这些脂质是否对自身免疫有功能影响，我们给多发性硬化症小鼠实验性变态反应性脑脊髓炎(EAE)小鼠注射了磷酸化二氢神经酰胺。我们发现，这些脂质，特别是磷乙醇胺二氢神经酰胺(PE-DHC)组分，显著增强了EAE。在机制上，PE DHC增强缺乏自然杀伤T细胞的小鼠的EAE，但不能增强Toll样受体2(TLR2)缺陷小鼠的EAE，并在体外以TLR2依赖的方式诱导树突状细胞分泌IL-6。最后，PE DHC治疗的EAE小鼠显示脊髓Foxp3T细胞的百分比降低，这表明这些脂质可能影响适应性免疫反应的调节方面。总体而言，我们的结果表明，来自常见人类细菌的磷酸化二氢神经酰胺作为TLR2配体发挥功能，并可能在人类自身免疫性疾病中发挥以前未被认识到的作用。(Am J Pathol 2009175：2430-2438；DOI：10.2353/ajpath.2009.090544)
Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they may play a role in human inflammatory disease. To investigate whether these lipids have functional effects on autoimmunity, we administered phosphorylated dihydroceramides to mice with the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). We find that these lipids, and particularly the phosphoethanolamine dihydroceramide (PE DHC) fraction, significantly enhanced EAE. Mechanistically, PE DHC enhances EAE in mice lacking natural killer T cells, fails to enhance EAE in Toll-like receptor 2 (TLR2)deficient mice and, in vitro , induces dendritic cell interleukin-6 secretion in a TLR2-dependent manner. Finally, PE DHC-treated mice with EAE demonstrate a decreased percentage of spinal cord Foxp3 T cells, suggesting that these lipids may affect regulatory aspects of adaptive immune responses. Overall , our results suggest that phosphorylated dihydroceramides derived from common human bacteria function as TLR2 ligands and may play a previously unrecognized role in human autoimmune diseases. (Am J Pathol 2009, 175:2430–2438; DOI: 10.2353/ajpath.2009.090544)