Chemotaxis of mouse bone marrow neutrophils and dendritic cells is controlled by adp-ribose, the major product generated by the CD38 enzyme reaction.
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.
Partida-Sanchez
Santiago
S
Trudeau Institute, Saranac Lake, NY 12983, USA.
Gasser
Andreas
A
Fliegert
Ralf
R
Siebrands
Cornelia C
CC
Dammermann
Werner
W
Shi
Guixiu
G
Mousseau
Betty J
BJ
Sumoza-Toledo
Adriana
A
Bhagat
Harivadan
H
Walseth
Timothy F
TF
Guse
Andreas H
AH
Lund
Frances E
FE
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000276:immunology; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000031:analogs & derivatives / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013997:Time Factors
C526196:8-bromo-adenosine diphosphate ribose; D009243:NAD; D000246:Adenosine Diphosphate Ribose; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium