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.
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CD38 is thought to mediate immunity through antimicrobial functions, given that a major phenotype of Cd38-knockout mice is their inability to mount immune responses to bacteria.
“Additionally, CD38 is thought to mediate immunity through antimicrobial functions, given that a major phenotype of Cd38-knockout mice is their inability to mount immune responses to bacteria55.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [55]
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- Authors
- Partida-Sánchez, S., Cockayne, D. A., Monard, S., Jacobson, E. L., Oppenheimer, N., Garvy, B., Kusser, K., Goodrich, S., Howard, M., Harmsen, A., Randall, T. D., & Lund, F. E.
- Affiliations
- Roche (United States) (US)
- Trudeau Institute (US)
- University of Arizona (US)
- University of California, San Francisco (US)
- University of Kentucky (US)
- ChemoCentryx (United States) (US)
- Montana State University (US)
- Corresponding author
- Lund, Frances E.
- Venue
- Nature Medicine
- Published
- 2001-11
- Volume
- 7
- Issue
- 11
- Pages
- 1209-1216
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1560040722
- Cited by
- 450
- References
- 42
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 17 · 2023: 14 · 2022: 15 · 2021: 27 · 2020: 22 · 2019: 15 · 2018: 21 · 2017: 12 · 2016: 15 · 2015: 13 · 2014: 13 · 2013: 12 · 2012: 21
- FWCI
- 10.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- cyclic ADP-ribose, CD38, ADP-ribosyl cyclase, neutrophils, intracellular calcium release, extracellular calcium influx, neutrophil chemotaxis, fMLP, bacterial clearance, innate immunity, inflammation, bacterial infection susceptibility
- MeSH terms
- Adenosine Diphosphate Ribose, Animals, Antigens, Differentiation, Chemotaxis, Leukocyte, Lymphoid Tissue, Membrane Glycoproteins, Mice, Inbred C57BL, N-Formylmethionine Leucyl-Phenylalanine, NAD, NAD+ Nucleosidase, Neutrophils, Pneumococcal Infections, Ryanodine, Streptococcus pneumoniae, Antigens, CD, Mice, Knockout, Calcium Signaling, ADP-ribosyl Cyclase, Cyclic ADP-Ribose, Mice, ADP-ribosyl Cyclase 1
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