NEURONS PROMOTE MACROPHAGE PROLIFERATION BY PRODUCING TRANSFORMING GROWTH-FACTOR-BETA-2

The infiltration of bone marrow-derived macrophages into the CNS contr ibutes to growth and reactions of microglia during development or afte r brain injury. The proliferation of microglial cells is stimulated by colony-stimulating factor 1 (CSF-1), an astrocyte-produced growth fac tor that acts on mononuclear phagocytes. In the present study we have shown, using an in vitro model system, that rodent neurons obtained fr om the developing cerebral cortex produce a soluble factor that strong ly enhances the proliferation of macrophages cultured in the presence of CSF-1. Both macrophages isolated from the developing brain and thos e from the adult bone marrow were stimulated. Kinetic analyses of [H-3 ]thymidine incorporation into macrophages indicated that their respons e to the neuron-derived factor involved a shortening of the cycle of p roliferating cells. The effect of neurons on macrophages was blocked i n the presence of antibodies neutralizing transforming growth factor-b eta 2 (TGF-beta 2), whereas recombinant TGF-beta 2 stimulated macropha ge proliferation in the presence of CSF-1. Neuronal secretion of TGF-b eta 2 was confirmed by reverse transcription-PCR detection of TGF-beta 2 transcripts and immunodetection of the protein within neurons and i n their culture medium. in situ hybridization and immunohistochemical experiments showed neuronal expression of TGF-beta 2 in sections of ce rebral cortex obtained from 6-d-old rats, an age at which extensive de velopmental recruitment of macrophages occurs in this cerebral region. Altogether, our results provide direct evidence that neurons have the capacity to promote brain macrophage proliferation and demonstrate th e role of TGF-beta 2 in this neuronal function.