The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways.
The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways.
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DOI：
10.1096/fj.202002136r
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Vogel SN
中科院分区：
文献类型：
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作者：
Prantner D;Nallar S;Vogel SN
尽管先天免疫受体蛋白，晚期糖基化终产物受体（Receptor for Advanced Glycation End Products，RGP）已被广泛研究，但RGP因其在脓毒症中的潜在作用以及沿着许多其他慢性、非感染性起源的炎性疾病而重新受到关注。与其他先天免疫受体相反，例如，Toll样受体（TLR）识别来源于病原生物体的配体，这些配体统称为“病原体相关分子模式”（PAMP）或宿主来源的“损伤相关分子模式”（DAMP），已显示Toll样受体专门识别广泛的DAMP集合。历史上，这些DAMP已被证明是促炎性的。早期的研究表明，衔接分子MyD88可能对这种变化很重要。最近的研究进一步探索了这种炎症变化的机制。总体而言，新的结果表明，有广泛的串扰之间的寄生虫和TLR。三种典型的TLR配体，即晚期糖基化终产物（AGEs）、HMGB1和S100蛋白，均已显示在不同程度上激活TLR和TLR，以在体外模型中诱导炎症。与深入研究先天信号传导的任何领域一样，试剂纯度的障碍可能是文献中一些差异的原因，并且我们发现已广泛使用的商业抗体表现出高度的非特异性。尽管如此，已发表的证据的重要性使我们推测RAGE可能与细胞表面的TLR发生物理相互作用，通过MyD 88依赖性信号传导引发炎症。
Although the innate immune receptor protein, Receptor for Advanced Glycation End products (RAGE), has been extensively studied, there has been renewed interest in RAGE for its potential role in sepsis, along with a host of other inflammatory diseases of chronic, non-infectious origin. In contrast to other innate immune receptors, e.g., Toll-like receptors (TLRs), that recognize ligands derived from pathogenic organisms that are collectively known as “pathogen-associated molecular patterns” (PAMPs) or host-derived “damage-associated molecular patterns” (DAMPs), RAGE has been shown to recognize a broad collection of DAMPs exclusively. Historically, these DAMPs have been shown to be proinflammatory in nature. Early studies indicated that the adaptor molecule, MyD88, might be important for this change. More recent studies have explored further the mechanisms underlying this inflammatory change. Overall, the newer results have shown that there is extensive crosstalk between RAGE and TLRs. The three canonical RAGE ligands, Advanced Glycation End products (AGEs), HMGB1, and S100 proteins, have all been shown to activate both TLRs and RAGE to varying degrees in order to induce inflammation in in vitro models. As with any field that delves deeply into innate signaling, obstacles of reagent purity may be a cause of some of the discrepancies in the literature, and we have found that commercial antibodies that have been widely used exhibit a high degree of non-specificity. Nonetheless, the weight of published evidence has led us to speculate that RAGE may be physically interacting with TLRs on the cell surface to elicit inflammation via MyD88-dependent signaling.