Amiel Eyal, Alonso Anselmo, Uematsu Satoshi, Akira Shizuo, Poynter Matthew E, Berwin Brent
Department of Microbiology and Immunology, Dartmouth College, Lebanon, New Hampshire 03756, USA.
J Leukoc Biol. 2009 Apr;85(4):595-605. doi: 10.1189/jlb.1008631. Epub 2008 Dec 26.
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.
A类清道夫受体（SR-A）和Toll样受体（TLR）介导针对病原菌的早期免疫反应。SR-A和TLR分子在吞噬细胞上表达，并与革兰氏阴性菌和革兰氏阳性菌的共同配体相互作用；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，我们提供了基因和功能证据，表明配体特异性和TLR特异性刺激与SR-A协同作用以介导细菌吞噬作用。虽然已知SR-A完全缺失（SR-A(-/-)）会损害细菌清除，但在此我们鉴定出首个可归因于SR-A杂合性的缺陷：SR-A(+/-)TLR4(+/-)细胞和小鼠在清除革兰氏阴性大肠杆菌方面存在显著缺陷。这种表型是TLR信号事件所特有的，因为SR-A(+/-)TLR4(+/-)细胞在清除革兰氏阳性金黄色葡萄球菌方面并无缺陷，金黄色葡萄球菌含有细胞表面TLR2配体但缺乏TLR4配体。我们证明这是一种由多种TLR独立调节的全身性吞噬机制，类似于SR-A(+/-)TLR4(+/-)缺陷，SR-A(+/-)TLR2(+/-)细胞在摄取金黄色葡萄球菌方面存在缺陷。为此提供支持的是，我们表明SR-A(+/-)MyD88(+/-)细胞重现了在SR-A(+/-)TLR4(+/-)细胞中观察到的吞噬缺陷。这些数据首次确定，通过MyD88信号机制，TLR驱动的先天性免疫反应调节SR-A依赖的细菌吞噬作用。这些发现为先天性免疫细胞如何控制SR-A介导的转运提供了新的见解，并且首次证明SR-A和TLR表达的细微变化可显著影响宿主细菌清除。
