Pivotal Advance: Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis
Pivotal Advance: Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis
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DOI：
10.1189/jlb.1008631
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发表时间：
2009-04-01
影响因子：
5.5
通讯作者：
Berwin, Brent
中科院分区：
文献类型：
--
作者：
Amiel, Eyal;Alonso, Anselmo;Berwin, Brent
a类清道夫受体（SR-A）和TLR介导对致病菌的早期免疫反应。SR-A和TLR分子在吞噬细胞上表达，并与来自革兰氏阴性和革兰氏阳性细菌的常见配体相互作用；然而，TLR活性对sr - a介导的吞噬作用的贡献尚未得到直接评估。在此，我们提供了遗传和功能证据，证明配体和tlr特异性刺激与SR-A协同作用介导细菌吞噬。虽然已知SR-A（SR-A(-/-)）的完全缺失会损害细菌的清除，但在这里，我们确定了SR-A杂合性导致的第一个缺陷：SR-A(+/-)TLR4（+/-）细胞和小鼠在清除革兰氏阴性大肠杆菌方面明显受损。这种表型是TLR信号事件特异性的，因为SR-A(+/-)TLR4（+/-）细胞不缺乏对革兰氏阳性金黄色葡萄球菌的清除，后者含有细胞表面TLR2配体，但缺乏TLR4配体。我们证明这是一个全球性的吞噬机制，由多个tlr独立调节，类似于SR-A(+/-)TLR4（+/-）缺陷，SR-A(+/-)TLR2（+/-）细胞对金黄色葡萄球菌的摄取受损。为了支持这一点，我们发现SR-A(+/-)MyD88（+/-）细胞再现了SR-A(+/-)TLR4（+/-）细胞中观察到的吞噬缺陷。这些数据首次确定了tlr驱动的先天免疫反应，通过MyD88信号传导机制，调节sr - a依赖的细菌吞噬。这些发现为先天免疫细胞如何控制SR-A介导的转运提供了新的见解，并且首次证明SR-A和tlr表达的细微变化可以实质性地影响宿主细菌清除。j . Leukoc。生物学报。85:595-605；2009.
Class-A scavenger receptors (SR-A) and TLR mediate early immune responses against pathogenic bacteria. SR-A and TLR molecules are expressed on phagocytes and interact with common ligands from Gram-negative and Gram-positive bacteria; however, the contribution of TLR activity to SR-A-mediated phagocytosis has not been assessed directly. Herein, we provide genetic and functional evidence that ligand-and TLR-specific stimuli synergize with SR-A to mediate bacterial phagocytosis. Although complete loss of SR-A (SR-A(-/-)) is known to impair bacterial clearance, here we identify the first deficiency attributable to SR-A heterozygosity: SR-A(+/-)TLR4(+/-) cells and mice are impaired significantly in the clearance of Gram-negative Escherichia coli. This phenotype is specific to the TLR signaling event, as SR-A(+/-)TLR4(+/-) cells are not deficient for the clearance of Gram-positive Staphylococcus aureus bacteria, which contain cell-surface TLR2 ligands but lack TLR4 ligands. We demonstrate that this is a global, phagocytic mechanism, regulated independently by multiple TLRs, as analogous to the SR-A(+/-)TLR4(+/-) deficit, SR-A(+/-)TLR2(+/-) cells are impaired for S. aureus uptake. In support of this, we show that SR-A(+/-)MyD88(+/-) cells recapitulate the phagocytosis defect observed in SR-A(+/-)TLR4(+/-) cells. These data identify for the first time that TLR-driven innate immune responses, via a MyD88 signaling mechanism, regulate SR-A-dependent phagocytosis of bacteria. These findings provide novel insights into how innate immune cells control SR-A-mediated trafficking and are the first demonstration that subtle changes in the expression of SR-A and TLRs can substantially affect host bacterial clearance. J. Leukoc. Biol. 85: 595-605; 2009.