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
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ADP-ribosyl Cyclase
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ADP-ribosyl Cyclase 1
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Adenosine Diphosphate Ribose / analogs & derivatives*
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Adenosine Diphosphate Ribose / biosynthesis*
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Animals
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Antigens, CD*
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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Calcium Signaling / physiology*
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Chemotaxis, Leukocyte / drug effects
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Chemotaxis, Leukocyte / physiology*
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Cyclic ADP-Ribose
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Lymphoid Tissue / enzymology
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Lymphoid Tissue / immunology
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Membrane Glycoproteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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N-Formylmethionine Leucyl-Phenylalanine / pharmacology
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NAD / analogs & derivatives*
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NAD / pharmacology
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NAD+ Nucleosidase / genetics
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NAD+ Nucleosidase / metabolism*
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / physiology*
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Pneumococcal Infections / etiology
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Ryanodine / pharmacology
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Streptococcus pneumoniae / immunology
Substances
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Antigens, CD
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Antigens, Differentiation
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Membrane Glycoproteins
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NAD
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Cyclic ADP-Ribose
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Ryanodine
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Adenosine Diphosphate Ribose
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nicotinamide-8-bromoadenine dinucleotide
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N-Formylmethionine Leucyl-Phenylalanine
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ADP-ribosyl Cyclase
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Cd38 protein, mouse
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NAD+ Nucleosidase
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ADP-ribosyl Cyclase 1