Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1-deficient mice.
Listeria monocytogenes, a facultative intracellular bacterium, has been used extensively to study innate immune responses. Macrophages act as hosts for this bacterium as well as a major defense against it. Using mice homozygous for a null mutation (Csf1(op)) in the gene for the mononuclear phagocytic growth factor colony-stimulating factor 1 (CSF-1), we have demonstrated that CSF-1-regulated macrophages were essential to defend against a listerial infection. In the absence of CSF-1, monocytes were not recruited to the sites of infection due to the lack of synthesis of the macrophage chemoattractant chemokine MCP-1. In addition, there was no burst of interleukin-10 (IL-10) synthesis that has been shown to result in the egress of neutrophils from sites of infection. Consequently, neutrophils were not replaced by macrophages, and numerous neutrophil-filled microabscesses developed, followed by tissue destruction and death of the mice. In the CSF-1 nullizygous mice compared to wild-type mice, there was also a very low synthesis of gamma interferon (IFN-gamma), resulting in reduced macrophage activation. However, the concentrations of the IFN-gamma-inducing cytokines IL-12 and IL-18 at this bacterial load were similar in these mutant mice. In contrast, IL-6 concentrations were dramatically reduced. Administration of IL-6 to Csf1(op)/Csf1(op) mice significantly increased the synthesis of IFN-gamma and reduced the bacterial burden to a greater extent than treatment with IFN-gamma alone. These data indicate that IL-6 occupies a central role in the CSF-1-regulated macrophage response to L. monocytogenes.
Guleria
I
I
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA.
Pollard
J W
JW
D000038:Abscess; D000818:Animals; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D007371:Interferon-gamma / Q000096:biosynthesis / Q000627:therapeutic use; D015850:Interleukin-6 / Q000096:biosynthesis / Q000627:therapeutic use; D008088:Listeriosis / Q000188:drug therapy / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000627:therapeutic use; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000166:cytology*; D018417:Th1 Cells
D015850:Interleukin-6; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma