Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis

It is well known that microglial cells perform a key role in mediating infl ammatory processes, which are associated with neurodegenerative diseases su ch as multiple sclerosis (MS). In this study, we report that CD40 expressio n on microglia is greatly enhanced by a low dose (10 U/ml) of IFN-gamma. We also find that ligation of microglial CD40 by CD40L triggers a significant production of TNF-alpha. Activation of microglia by ligation of CD40 in th e presence of IFN-gamma results in cultured cortical neuronal injury, which is markedly attenuated by blockade of the CD40 pathway or neutralization o f TNF-alpha. Finally, we find significant levels of IFN-gamma and TNF-alpha in the medium of co-cultured activated CD4 + T cells and microglial cells, showing that microglia can supply the CD40 receptor to activated CD4 + T c ells and suggesting that this cellular interaction is a key event in MS pat hophysiology. (C) 1999 Elsevier Science B.V. All rights reserved.