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. 2001 Nov;7(11):1209-16. doi: 10.1038/nm1101-1209.

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.

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • Adenosine Diphosphate Ribose / analogs & derivatives*
  • Adenosine Diphosphate Ribose / biosynthesis*
  • Animals
  • Antigens, CD*
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • Calcium Signaling / physiology*
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / physiology*
  • Cyclic ADP-Ribose
  • Lymphoid Tissue / enzymology
  • Lymphoid Tissue / immunology
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • NAD / analogs & derivatives*
  • NAD / pharmacology
  • NAD+ Nucleosidase / genetics
  • NAD+ Nucleosidase / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / physiology*
  • Pneumococcal Infections / etiology
  • Ryanodine / pharmacology
  • Streptococcus pneumoniae / immunology

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Membrane Glycoproteins
  • NAD
  • Cyclic ADP-Ribose
  • Ryanodine
  • Adenosine Diphosphate Ribose
  • nicotinamide-8-bromoadenine dinucleotide
  • N-Formylmethionine Leucyl-Phenylalanine
  • ADP-ribosyl Cyclase
  • Cd38 protein, mouse
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1