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Abstract
Cyclic ADP ribose (cADPR) is a calcium-mobilizing metabolite that regulates intracellular calcium release and extracellular calcium influx. Although the role of cADPR in modulating calcium mobilization has been extensively examined, its potential role in regulating immunologic responses is less well understood. We previously reported that cADPR, produced by the ADP-ribosyl cyclase, CD38, controls calcium influx and chemotaxis of murine neutrophils responding to fMLF, a peptide agonist for two chemoattractant receptor subtypes, formyl peptide receptor and formyl peptide receptor-like 1. In this study, we examine whether cADPR is required for chemotaxis of human monocytes and neutrophils to a diverse array of chemoattractants. We found that a cADPR antagonist and a CD38 substrate analogue inhibited the chemotaxis of human phagocytic cells to a number of formyl peptide receptor-like 1-specific ligands but had no effect on the chemotactic response of these cells to ligands selective for formyl peptide receptor. In addition, we show that the cADPR antagonist blocks the chemotaxis of human monocytes to CXCR4, CCR1, and CCR5 ligands. In all cases, we found that cADPR modulates intracellular free calcium levels in cells activated by chemokines that induce extracellular calcium influx in the apparent absence of significant intracellular calcium release. Thus, cADPR regulates calcium signaling of a discrete subset of chemoattractant receptors expressed by human leukocytes. Since many of the chemoattractant receptors regulated by cADPR bind to ligands that are associated with clinical pathology, cADPR and CD38 represent novel drug targets with potential application in chronic inflammatory and neurodegenerative disease.
Highlights
We previously reported that Cyclic ADP ribose (cADPR), produced by the ADP-ribosyl cyclase, CD38, controls calcium influx and chemotaxis of murine neutrophils responding to fMLF, a peptide agonist for two chemoattractant receptor subtypes, formyl peptide receptor and formyl peptide receptor-like 1
To test whether 8-Br-cADPR inhibits the migration of mouse neutrophils to other mFPR1 or mFPR2 ligands, we measured the chemotactic response of 8-Br-cADPR-treated neutrophils isolated from the bone marrow of C57BL/6 and mFPR1deficient mice (Ref. 23; mFPR1 KO) to peptides that activate mFPR1 and/or mFPR2
These data show that a cADPR antagonist can be used to inhibit the migration of mouse bone marrow neutrophils to a variety of formyl peptide receptor (FPR) ligands and suggest that cADPR regulates the signaling of both mFPR1 and mFPR2 in mouse neutrophils
Summary
To determine whether cADPR regulates signaling through FPR, FPRL1, or both receptors, we have examined the effect of cADPR antagonists or CD38 substrate analogues on the calcium and chemotactic responses of human neutrophils and monocytes to FPR and FPRL1-specific ligands as well as to a number of additional inflammatory and homeostatic chemokines. 8-Br-cADPR treatment had minimal effect on the calcium response of human neutrophils stimulated with the FPR-specific ligands fMLF and T20 peptide (Fig. 4B).
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