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.

• Authors: S Partida-Sánchez, D A Cockayne, S Monard, E L Jacobson, N Oppenheimer, B Garvy, K Kusser, S Goodrich, M Howard, A Harmsen, T D Randall, F E Lund
• Journal: Nature medicine (Nat Med) Vol. 7 Issue 11 Pg. 1209-16 (Nov 2001) ISSN: 1078-8956 [Print] United States
• PMID: 11689885 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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