title: The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses.
abstract: Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi). Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response. Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.
authors.affiliation: Sir William Dunn School of Pathology, Oxford University, Oxford, United Kingdom.
authors.forename: Leanne
authors.initials: L
authors.lastname: Peiser
authors.forename: Menno P J
authors.initials: MP
authors.lastname: De Winther
authors.forename: Katherine
authors.initials: K
authors.lastname: Makepeace
authors.forename: Michael
authors.initials: M
authors.lastname: Hollinshead
authors.forename: Philip
authors.initials: P
authors.lastname: Coull
authors.forename: Joyce
authors.initials: J
authors.lastname: Plested
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: E Richard
authors.initials: ER
authors.lastname: Moxon
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D029721:Drosophila Proteins; D008050:Lipid A / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008589:Meningococcal Infections / Q000209:etiology / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009345:Neisseria meningitidis / Q000276:immunology* / Q000472:pathogenicity*; D010587:Phagocytosis; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D029721:Drosophila Proteins; D008050:Lipid A; D008562:Membrane Glycoproteins; C495140:Msr1 protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors