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
Santiago Partida-Sánchez1, Debra A. Cockayne2, Simon Monard1, Elaine L. Jacobson3, Norman Oppenheimer4, Beth Garvy5, Kim Kusser1, Stephen Goodrich1, Maureen Howard6, Allen Harmsen7, Troy D. Randall1
& Frances E. Lund1
1
Trudeau Institute, Saranac Lake, New York, USA
2
Roche Bioscience, Neurobiology Unit, Palo Alto, California, USA
3
Department of Pharmacology and Toxicology and Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA
4
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
5
Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
6
Chemocentryx, San Carlos, California, USA
7
Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA
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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