Monocyte and macrophage functions in M-CSF-deficient op/op mice during experimental leishmaniasis

Abstract: Mice with a naturally occurring Csfmop/ Csfmop (op/op) gene mutation lack functional mac-rophage-colony stimulating factor (M-CSF) and are deficient of M-CSF-derived macrophages. They are severely monocytopenic, and their remaining M-CSF-independent macrophages were shown to differ in dif-ferentiation and distinct functions when compared with phenotypically normal mice of the same back-ground. It is not known if osteopetrosis mice (op/op mice) are able to mount a specific immune response against intracellular pathogens, as this would require complex effector functions by macrophages. We therefore investigated the ability of op/op mice and their M-CSF-independent macrophages to combat in-fection with Leishmania major. op/op mice retained the ability to resist an infection with L. major by mounting a T helper cell type 1 cell response, elimi-nating parasites and resolving the lesions. Macro-phages from op/op mice were able to sufficiently per-form effector functions in vitro, such as phagocytosis, production of leishmanicidal nitric oxide (NO), kill-ing of parasites, and release of interleukin (IL)-12. There were quantitative differences, as M-CSF-de-rived macrophages from hematopoietic organs of control mice showed significantly higher rates of phagocytosis and higher NO release after stimulation with lipopolysaccharides than corresponding macro-phages from op/op mice. In contrast, when peritone-ally elicited macrophages were used, those from op/op mice revealed a stronger response than those from control mice with regard to release of NO or IL-12. These differences suggest that M-CSF-inde-pendent maturation of op/op monocytes subsequent to their release from hematopoietic tissue exerts in-fluence on their effector functions. However, M-CSF or M-CSF-derived macrophages are not necessary for an effective immune response against L. major