Chemotaxis of Mouse Bone Marrow Neutrophils and Dendritic Cells Is Controlled by ADP-Ribose, the Major Product Generated by the CD38 Enzyme Reaction
Abstract
The ectoenzyme CD38 catalyzes the production of cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from its substrate, NAD+. Both products of the CD38 enzyme reaction play important roles in signal transduction, as cADPR regulates calcium release from intracellular stores and ADPR controls cation entry through the plasma membrane channel TRPM2. We previously demonstrated that CD38 and the cADPR generated by CD38 regulate calcium signaling in leukocytes stimulated with some, but not all, chemokines and controls leukocyte migration to inflammatory sites. However, it is not known whether the other CD38 product, ADPR, also regulates leukocyte trafficking In this study we characterize 8-bromo (8Br)-ADPR, a novel compound that specifically inhibits ADPR-activated cation influx without affecting other key calcium release and entry pathways. Using 8Br-ADPR, we demonstrate that ADPR controls calcium influx and chemotaxis in mouse neutrophils and dendritic cells activated through chemokine receptors that rely on CD38 and cADPR for activity, including mouse FPR1, CXCR4, and CCR7. Furthermore, we show that the calcium and chemotactic responses of leukocytes are not dependent on poly-ADP-ribose polymerase 1 (PARP-1), another potential source of ADPR in some leukocytes. Finally, we demonstrate that NAD+ analogues specifically block calcium influx and migration of chemokine-stimulated neutrophils without affecting PARP-1-dependent calcium responses. Collectively, these data identify ADPR as a new and important second messenger of mouse neutrophil and dendritic cell migration, suggest that CD38, rather than PARP-1, may be an important source of ADPR in these cells, and indicate that inhibitors of ADPR-gated calcium entry, such as 8Br-ADPR, have the potential to be used as anti-inflammatory agents.
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CD38 regulates immune-cell homing, innate immune responses to pathogens and antitumour immunity.
“Previous studies have reported that CD38 regulates immune-cell homing, innate immune responses to pathogens and antitumour immunity63-65.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [65]
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Self-citation
- Authors
- Partida-Sanchez, S., Gasser, A., Fliegert, R., Siebrands, C. C., Dammermann, W., Shi, G., Mousseau, B. J., Sumoza-Toledo, A., Bhagat, H., Walseth, T. F., Guse, A. H., & Lund, F. E.
- Affiliations
- Trudeau Institute , Saranac Lake, NY 12983
- University Medical Center Hamburg-Eppendorf (DE)
- Trudeau Institute (US)
- Department of Pediatrics, Columbus Children’s Research Institute , Columbus, OH 43205
- Abigail Wexner Research Institute (US)
- University of Minnesota (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-12-01
- Volume
- 179
- Issue
- 11
- Pages
- 7827-7839
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2118270110
- Cited by
- 144
- References
- 72
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 10 · 2019: 7 · 2018: 16 · 2017: 9 · 2016: 7 · 2015: 3 · 2014: 11 · 2013: 5 · 2012: 12
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Minnesota
- National Institute on Drug Abuse (DA-11806, P50DA011806)
- National Institute of Allergy and Infectious Diseases (AI-057996, R01AI057996)
- 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
- ADP-ribose, CD38, cyclic ADP-ribose, neutrophil chemotaxis, dendritic cell migration, leukocyte migration, TRPM2, calcium influx, chemokine receptors, CXCR4, CCR7, FPR1, PARP1, NAD+ analogues, anti-inflammatory agents, second messengers
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Adenosine Diphosphate Ribose, Animals, Bone Marrow Cells, Calcium, Cell Line, Chemotaxis, Dendritic Cells, Leukocytes, Mice, Inbred C57BL, NAD, Neutrophils, Poly(ADP-ribose) Polymerases, Sensitivity and Specificity, Structure-Activity Relationship, Time Factors, Mice, Knockout, Mice, ADP-ribosyl Cyclase 1
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