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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heterozygote
  • Immunity, Innate
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / immunology*
  • Phagocytosis / immunology*
  • Receptor Cross-Talk
  • Scavenger Receptors, Class A / deficiency
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / immunology*
  • Staphylococcus aureus / immunology
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptors / immunology*


  • Myeloid Differentiation Factor 88
  • Scavenger Receptors, Class A
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors