Necrosis-induced TLR3 Activation Promotes TLR2 Expression in Gingival Cells
Necrosis-induced TLR3 Activation Promotes TLR2 Expression in Gingival Cells
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DOI：
10.1177/0022034515589289
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发表时间：
2015-08-01
影响因子：
7.6
通讯作者：
Murakami, S.
中科院分区：
文献类型：
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作者：
Mori, K.;Yanagita, M.;Murakami, S.
损伤相关分子模式（DAMP），从受损或死亡细胞释放的内源性分子，引起非微生物病原体诱导的无菌炎症。牙周病是由口腔微生物引起的感染性疾病;然而，在某些情况下，DAMP可能在宿主细胞识别病原体相关分子模式之前启动炎症反应。在这里，我们表明，坏死细胞上清液（NCS）作为一个内源性的危险信号时，从坏死的上皮细胞暴露于反复冻融释放。NCS含有RNA并刺激牙龈上皮细胞和牙龈成纤维细胞产生炎性细胞因子白细胞介素6（IL-6）和IL-8。靶向敲除这些细胞中的Toll样受体3（TLR 3）显著抑制NCS诱导IL-6和IL-8产生的能力。上皮细胞和成纤维细胞识别来自异源细胞的NCS。有趣的是，TLR 3的激活，而不是其他TLRs，诱导牙龈上皮细胞中TLR 2 mRNA的表达和蛋白质，并与NCS或聚肌苷酸：聚胞苷酸（Poly（I：C）），一种强TLR 3激活剂，预处理增强炎症细胞因子的产生诱导随后刺激牙龈卟啉单胞菌（牙龈卟啉单胞菌）脂多糖，TLR 2激动剂。此外，NCS降低了上皮紧密连接分子Closoccludens 1和occludin的表达，并增加了上皮紧密连接的通透性。这些研究结果表明，内源性危险信号分子，如自坏死细胞释放的RNA被TLR 3识别，并且随后牙周区室中TLR 2表达的增加，如牙龈上皮细胞和牙龈成纤维细胞，可能会增强对TLR 2识别的牙周病微生物的炎症反应，如牙龈卟啉单胞菌，这也会破坏上皮屏障功能。因此，DAMPs可能参与牙周病的发展和延长。
Damage-associated molecular patterns (DAMPs), endogenous molecules released from injured or dying cells, evoke sterile inflammation that is not induced by microbial pathogens. Periodontal diseases are infectious diseases caused by oral microorganisms; however, in some circumstances, DAMPs might initiate inflammatory responses before host cells recognize pathogen-associated molecular patterns. Here, we showed that the necrotic cell supernatant (NCS) functioned as an endogenous danger signal when released from necrotic epithelial cells exposed to repeat freeze thawing. The NCS contained RNA and stimulated the production of inflammatory cytokines interleukin 6 (IL-6) and IL-8 from gingival epithelial cells and gingival fibroblasts. Targeted knockdown of Toll-like receptor 3 (TLR3) in these cells significantly suppressed the ability of the NCS to induce IL-6 and IL-8 production. Epithelial cells and fibroblasts recognized the NCS from heterologous cells. Interestingly, the activation of TLR3, rather than other TLRs, induced TLR2 mRNA expression and proteins in gingival epithelial cells, and pretreatment with the NCS or polyinosinic: polycytidylic acid (Poly(I:C)), a strong TLR3 activator, enhanced inflammatory cytokine production induced by subsequent stimulation with Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide, a TLR2 agonist. Moreover, the NCS reduced the expression of epithelial tight junction molecules zona occludens 1 and occludin and increased the permeability of epithelial tight junctions. These findings suggest that endogenous danger signal molecules such as self-RNA released from necrotic cells are recognized by TLR3 and that a subsequent increase of TLR2 expression in periodontal compartments such as gingival epithelial cells and gingival fibroblasts may enhance the inflammatory response to periodontopathic microbes recognized by TLR2 such as P. gingivalis, which also disrupts epithelial barrier functions. Thus, DAMPs may be involved in the development and prolongation of periodontal disease.