title: Pivotal Advance: Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis.
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.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth College, Lebanon, New Hampshire 03756, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Amiel
authors.forename: Anselmo
authors.initials: A
authors.lastname: Alonso
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Brent
authors.initials: B
authors.lastname: Berwin
mesh_terms: D000818:Animals; D006579:Heterozygote; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D020239:Receptor Cross-Talk; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D053594:Myeloid Differentiation Factor 88; D051117:Scavenger Receptors, Class A; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors