Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1008631 on December 26, 2008

Published online before print December 26, 2008
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(Journal of Leukocyte Biology. 2009;85:595-605.)
© 2009 by Society for Leukocyte Biology

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

Eyal Amiel*, Anselmo Alonso*, Satoshi Uematsu{dagger}, Shizuo Akira{dagger}, Matthew E. Poynter{ddagger} and Brent Berwin*,1

* Department of Microbiology and Immunology, Dartmouth College, Lebanon, New Hampshire, USA;
{dagger} Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
{ddagger} Vermont Lung Center and Department of Medicine, University of Vermont, Burlington, Vermont, USA

1 Correspondence: Department of Microbiology and Immunology, Dartmouth College, 1 Medical Center Drive, Lebanon, NH 03756, USA. E-mail: berwin{at}dartmouth.edu

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.

Key Words: innate immunity • dendritic cells • E. coli • trafficking




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