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and Activation-Induced Cell Death Dual Role of CD38 in Microglial Activation

Microglia, the resident immune cells of the CNS, are normally quiescent but become activated after infection or injury. Their properties then change, and they promote both repair and damage processes. The extent of microglial activation is regulated, in part, by activation-induced cell death (AICD). Although many apoptotic aspects of the microglial AICD mechanism have been elucidated, little is known about the connection between the activation step and the death process. Using mouse primary microglial cultures, we show that the ectoenzyme CD38, via its calcium-mobilizing metabolite cyclic-ADP-ribose (cADPR), helps promote microglial activation and AICD induced by LPS plus IFN- (cid:1) (LPS/IFN- (cid:1) ), suggesting that CD38 links the two processes. Accord-ingly, CD38 expression and activity, as well as the intracellular calcium concentration ([Ca 2 (cid:2) ] i ) in the primary microglia were increased by LPS/IFN- (cid:1) treatment. Moreover, CD38 deﬁciency or treatment with cADPR antagonists conferred partial resistance to LPS/IFN- (cid:1) -induced AICD and also reduced [Ca 2 (cid:2) ] i . Microglial activation, indicated by induced expression of NO synthase-2 mRNA and production of NO, secretion and mRNA expression of TNF- (cid:3) and IL-12 p40, and expression of IL-6 mRNA, was attenuated by CD38 deﬁciency or cADPR-antagonist treatment. The observed effects of CD38 on microglial activation are probably mediated via a cADPR-dependent increase in [Ca 2 (cid:2) ] i and the effect on AICD by regulation of NO production. Our results thus suggest that CD38 signiﬁcantly affects regulation of the amount and function of activated microglia, with important consequences Taken together, these results suggest that CD38 regulates the LPS/IFN- (cid:3) -induced AICD in primary microglia, and that this effect is due, at least in part, to the enzymatic activity of CD38 via its production of cADPR.