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Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo

Abstract

Cyclic ADP-ribose is believed to be an important calcium-mobilizing second messenger in invertebrate, mammalian and plant cells. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cyclic ADP-ribose in vivo. Using CD38-deficient mice, we demonstrate that the loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38-deficient neutrophils to directionally migrate to the site of infection. Furthermore, we show that cyclic ADP-ribose can directly induce intracellular Ca++ release in neutrophils and is required for sustained extracellular Ca++ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP). Finally, we demonstrate that neutrophil chemotaxis to fMLP is dependent on Ca++ mobilization mediated by cyclic ADP-ribose. Thus, CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses.

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Figure 1: Cd38−/− mice are more susceptible to S. pneumoniae infection.
Figure 2: Cd38−/− neutrophils are not recruited to the infection site and do not chemotax toward bacterially derived chemoattractants.
Figure 3: CD38 expressing neutrophils produce cADPR and release intracellular Ca++ in response to cADPR and ryanodine.
Figure 4: CD38-catalyzed cADPR regulates intracellular Ca++ release, extracellular Ca++ influx and chemotaxis in neutrophils.
Figure 5: An NAD+ analog regulates Ca++ influx and chemotaxis in fMLP-activated neutrophils.

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Acknowledgements

We thank D. Coyle and J. Brennan for technical help; E. Gosselin for providing human neutrophils; and T. Charbonneau and H. Petty for helpful discussions.

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Correspondence to Frances E. Lund.

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Partida-Sánchez, S., Cockayne, D., Monard, S. et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med 7, 1209–1216 (2001). https://doi.org/10.1038/nm1101-1209

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