ROLE OF COLONY-STIMULATING FACTOR-I IN THE ESTABLISHMENT AND REGULATION OF TISSUE MACROPHAGES DURING POSTNATAL-DEVELOPMENT OF THE MOUSE

Colony stimulating factor-1 (CSF-1) regulates the survival, proliferat ion and differentiation of mononuclear phagocytes. The osteopetrotic ( op/op) mutant mouse is devoid of CSF-1 due to an inactivating mutation in the CSF-1 gene and is deficient in several mononuclear phagocyte s ubpopulations. To analyze more fully the requirement for CSF-1 in the establishment and maintenance of mononuclear phagocytes, the postnatal development of cells bearing the macrophage marker antigens F4/80 and MOMA-1, in op/op mice and their normal (+/op or +/+) littermates, wer e studied during the first three months of life. In normal mice, maxim um expression of tissue F4/80+ cells was generally correlated with the period of maximum organogenesis and/or cell turnover. Depending on th e tissue, the F4/80+ cell density either decreased, transiently increa sed or gradually increased with age. In op/op mice, tissues that norma lly contain F4/80+ cells could be classified into those in which F4/80 + cells were absent and those in which the F4/80+ cell densities were either reduced, normal or initially normal then subsequently reduced. To assess which F4/80+ populations were regulated by circulating CSF-1 in normal mice, op/op mice in which the circulating CSF-1 concentrati on was restored to above normal levels by daily subcutaneous injection of human recombinant CSF-1 from day 3 were analyzed. These studies su ggest that circulating CSF-1 exclusively regulates both the F4/80+ cel ls in the liver, spleen and kidney and the MOMA-1+ metallophilic macro phages in the spleen. Macrophages of the dermis, bladder, bone marrow and salivary gland, together with a subpopulation in the gut, were par tially restored by circulating CSF-1, whereas macrophages of the muscl e, tendon, periosteum, synovial membrane, adrenals and the macrophages intimately associated with the epithelia of the digestive tract, were not corrected by restoration of circulating CSF-1, suggesting that th ey are exclusively locally regulated by this growth factor. Langerhans cells, bone marrow monocytes and macrophages of the thymus and lymph nodes were not significantly affected by circulating CSF-1 nor decreas ed in op/op mice, consistent with their regulation by other growth fac tors. These results indicate that important differences exist among mo nonuclear phagocytes in their dependency on CSF-1 and the way in which CSF-1 is presented to them. They also suggest that the prevalent role of CSF-1 is to influence organogenesis and tissue turnover by stimula ting the production of tissue macrophages with local trophic and/or sc avenger (physiological) functions. Macrophages involved in inflammator y and immune (pathological) responses appear to be dependent on other factors for their ontogenesis and function. This study provides a base from which to analyze further the mechanisms of regulation and physio logical roles of CSF-l-dependent tissue macrophages.