MECHANISMS OF TROPHIN AND TOXIN ELABORATION BY MICROGLIA

Microglia have often been implicated in release of cytotoxic agents during CNS inflammation and injury. However, microglia also elaborate trophic factors. Little is known about the regulation and the role of these factors. Our goal is to delineate molecular mechanisms underlying microglial function and elucidate microglial trophic and toxic effects in inflammation and injury. Neurotrophins are of particular interest as our observations indicate that microglia both express and respond to trophins. Trophins induce proliferation, phagocytosis and morphologic changes associated with cellular activation. The aim of this study is to define microglial populations that produce toxins and trophic factors, in particular neurotrophins, to investigate the regulation of microglial neurotrophin expression and to delineate the effects of trophins on microglial cells. To characterize microglial subpopulations that produce toxins and tophic factors, the effects of microglial cell lines on neuronal and oligodendrocyte survival will be examined. Cultures will be used to study regulation of trophin expression, especially by microglial activators. Two models of injury that induce different microglial and neuronal reactions, the facial nerve transection and toxic ricin injection will be employed to investigate the regulation of microglial trophin expression following cellular activation, in vivo. Trophins also alter microglial function in vitro. We will investigate whether microglia respond to BDNF and NT-3, in vivo. The effects of neurotrophins on microglial proliferation will be studied by intraventricular administration of trophins followed by sc injections of 3H-thymidine. Cells will be visualized by immunocytochemistry and autoradiography. Proliferating microglia along the ventricular lining will be quantified. The effects of NT-3 on gene expression will also be determined by differential display and DNA sequence analysis, utilizing microglial cell lines and primary cultures to define mechanism involved in NT-3 induced alteration in microglial function. Delineation of molecular mechanisms underlying microglial activation and elucidation of microglial trophic and toxic actions may provide insights into processes associated with CNS inflammation and injury Attenuation of toxin production and enhancement of trophin elaboration may offer therapeutic approaches to promote survival of neurons and glia affected by inflammatory diseases of the nervous system or injury.