Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system

Tissue plasminogen activator mediates excitotoxin-induced neurodegeneration and microglial activation in the mouse hippocampus. Here we show that tiss ue plasminogen activator (tPA) acts in a protease-independent manner to mod ulate the activation of microglia, the cells of the central nervous system with macrophage properties. Cultured microglia from tPA-deficient mice can phagocytose as efficiently as wild-type microglia, However, tPA-deficient m icroglia in mixed cortical cultures exhibit attenuated activation in respon se to lipopolysaccharide, as judged by morphological changes, increased exp ression of the activation marker F4/80 and the release of the proinflammato ry cytokine tumor necrosis factor-alpha, When tPA is added to tPA deficient cortical cultures prior to endotoxin stimulation, microglial activation is restored to levels comparable to that observed in wild-type cells, Proteol ytically-inactive tPA can also restore activation of tPA-deficient microgli a in culture and in vivo. However, this inactive enzyme does not restore su sceptibility of tPA-deficient hippocampal neurons to excitotoxin-mediated c ell death. These results dissociate two different functions of tPA: inactiv e enzyme can mediate microglial activation, whereas proteolytically-compete nt protein also promotes neuronal degeneration. Thus tPA is identified as a new cytokine in the central nervous system.