Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America.
Physical Chemistry and Applied Spectroscopy, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
PLoS One. 2018 Jun 14;13(6):e0198531. doi: 10.1371/journal.pone.0198531. eCollection 2018.
Recognition of Pathogen-associated Molecular Patterns (PAMPs) by Toll-like receptors is central to innate immunity. Many bacterial PAMPs such as lipopolysaccharide (LPS) and lipoteichoic acid have amphiphilic properties. The hydrophobicity of amphiphilic PAMPs contributes to increasing entropy and causes these molecules to self-aggregate or bind host carrier proteins in aqueous physiological environments. The goal of this work was to determine how innate immune signaling is impacted by physical presentation and association of amphiphilic PAMPs with serum carrier proteins, using LPS as an example molecule. Specifically, we measured LPS-induced cytokine profiles in murine macrophages when the antigen was presented associated with the various serum carrier proteins in serum versus a serum-depleted system. Our study demonstrates that the observed cytokine profiles are dramatically different when LPS is presented in buffer, versus in serum when it is associated with proteins, specifically with respect to inhibition of pro-inflammatory cytokines in the latter. These studies suggest that LPS-mediated cytokine expression is dependent on its presentation in physiological systems. The amphiphilicity of bacterial PAMPs and consequent association with lipoproteins is a feature, which should be taken into account in the design of in vitro experiments. Further studies of the interdependencies of different serum carriers can identify pathways for drug delivery and diagnostics.
模式识别受体（Toll-like receptors）对病原体相关分子模式（Pathogen-associated Molecular Patterns，PAMPs）的识别是先天免疫的核心。许多细菌 PAMPs 具有两亲性，如脂多糖（lipopolysaccharide，LPS）和脂磷壁酸（lipoteichoic acid）。两亲性 PAMPs 的疏水性有助于增加熵，导致这些分子在水相生理环境中自聚集或与宿主载体蛋白结合。本工作旨在使用 LPS 作为示例分子，确定先天免疫信号如何受到两亲性 PAMPs 与血清载体蛋白的物理呈现和关联的影响。具体而言，我们测量了 LPS 诱导的小鼠巨噬细胞细胞因子谱，当抗原与血清中的各种血清载体蛋白相关联时，与在血清耗尽系统中相比。我们的研究表明，当 LPS 与蛋白质结合而不是在缓冲液中呈现时，观察到的细胞因子谱差异很大，特别是在后一种情况下，促炎细胞因子的抑制作用更为明显。这些研究表明，LPS 介导的细胞因子表达依赖于其在生理系统中的呈现。细菌 PAMPs 的两亲性及其与脂蛋白的关联是一个特征，在设计体外实验时应予以考虑。进一步研究不同血清载体的相互依存关系，可以确定药物输送和诊断的途径。
