Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antimicrobial host defense, although direct proof has been lacking. Here we test this hypothesis in mice lacking the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption. FPR-/- mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes, as measured by increased mortality compared with wild-type littermates. FPR-/- mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity. Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N-formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR-/- mice. These results indicate that FPR functions in antibacterial host defense in vivo.
Gao
J L
JL
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. jgao@nih.gov
Lee
E J
EJ
Murphy
P M
PM
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007958:Leukocyte Count; D008089:Listeria monocytogenes / Q000302:isolation & purification; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D008099:Liver / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000382:microbiology