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 use d extensively to study innate immune responses. Macrophages act as hosts fo r this bacterium as well as a major defense against it, Using mice homozygo us for a null mutation (Csf1(op)) in the gene for the mononuclear phagocyti c growth factor colony-stimulating factor 1 (CSF-1), we have demonstrated t hat CSF-l-regulated macrophages were essential to defend against a listeria l infection. In the absence of CSF-1, monocytes were not recruited to the s ites of infection due to the lack of synthesis of the macrophage chemoattra ctant chemokine MCP-1. In addition, there was no burst of interleukin-10 (I L-10) synthesis that has been shown to result in the egress of neutrophils from sites of infection. Consequently, neutrophils were not replaced by mac rophages, 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 i nterferon (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 c oncentrations were dramatically reduced. Administration of IL-6 to Csf1(op) /Csf1(op) mice significantly increased the synthesis of IFN-gamma and reduc ed the bacterial burden to a greater extent than treatment with IFN-gamma a lone. These data indicate that IL-6 occupies a central role in the CSF-l-re gulated macrophage response to L. monocytogenes.