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Pivotal Advance: Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis

By Eyal Amiel, Anselmo Alonso, Satoshi Uematsu, Shizuo Akira, Matthew E. Poynter and Brent Berwin

Abstract

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

Topics: Pivotal Advance
Publisher: The Society for Leukocyte Biology
OAI identifier: oai:pubmedcentral.nih.gov:2656429
Provided by: PubMed Central
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