Cytokine regulation of the macrophage (Mφ) system studied using the colony stimulating factor-1-deficient op/op mouse

The macrophage (Mφ) lineage is more complex than other myeloid lineages of hematopoietic cells and includes strikingly different end cells such as Kupffer cells, alveolar Mφ, histiocytes, serosal Mφ, synovial type A cells, microglia, osteoclasts, and possibly dendritic cells. These cells are formed under the influence of primary Mφ growth factors such as colony stimulating factor (CSF)-1, granulocyte-Mφ (GM)-CSF, and interleukin-3. The dissection of the system has been greatly facilitated by discovery of the osteopetrotic op/op mouse, which has a spontaneous knockout of the gene for CSF-1 and possesses generalized but differential deficiency of various local subpopulations of Mφ. Studies using this model indicate that the Mφ lineage is split into CSF-1-dependent and CSF-1-independent cells that are largely independently regulated. These contribute variably to different local populations and have largely, but not totally, overlapping functions. Both CSF-1 and GM-CSF are responsible for transition of cells of the Mφ lineage from bone marrow to blood, and from blood to tissues, and have a critical extramedullary role. Regulation of the Mφ system by CSF-1 is complex, with some local populations dependent on circulating CSF-1 and some supported exclusively by locally produced CSF-1. Colony stimulating factor-1-dependent Mφ are not required for the generation of a specific immune response. Instead, most likely they play a regulatory role in various tissue reactions including responses to bacterial infection, neoplasia, and atherosclerosis. A hypothetical major role of CSF-1-independent Mφ is to collaborate with lymphocytes in mounting an immune response. These issues need further exploration using animals with knockouts of genes for other Mφ growth and activation factors and their receptors.