The Journal of Experimental Medicine
IN Cell Analyzer 2000
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© The Rockefeller University Press, 0022-1007/1999/2/657/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 4, February 15, 1999 657-662

Articles

Impaired Antibacterial Host Defense in Mice Lacking the N-formylpeptide Receptor

Ji-Liang Gao*, Eric J. Lee{ddagger}, and Philip M. Murphy*

From the * Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, and the {ddagger} Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

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.

Key Words: chemotaxis • Listeria • inflammation • chemoattractant • neutrophil

Address correspondence to Ji-Liang Gao, Laboratory of Host Defenses, NIAID, Bldg. 10, Rm. 11N113, National Institutes of Health, Bethesda, MD 20892. Phone: 301-496-2877; Fax: 301-402-4369; E-mail: jgao{at}nih.gov

Abbreviations used: fMLF, formyl-methionyl-leucyl-phenylalanine; FPR, high affinity N-formylpeptide receptor; FPRL1, low affinity N-formylpeptide receptor or lipoxin A4 receptor; MIP, macrophage inflammatory protein; ORF, open reading frame; TP neutrophils, thioglycollate-elicited peritoneal neutrophils.


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