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-Sánchez, Debra A. Cockayne, Simon Monard, Elaine L. Jacobson, Norman Oppenheimer, Beth Garvy, Kim Kusser, Stephen Goodrich, Maureen Howard, Allen Harmsen, Troy D. Randall, Frances E. Lund

Research output: Contribution to journalArticlepeer-review

390 Scopus citations

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.

Original languageEnglish
Pages (from-to)1209-1216
Number of pages8
JournalNature Medicine
Volume7
Issue number11
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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