Chemotaxis and calcium responses of phagocytes to formyl peptide receptor ligands is differentially regulated by cyclic ADP ribose.

PARTIDA-SANCHEZ, S.; IRIBARREN P; MORENO-GARCIA, M. E.; GAO, L.; MURPHY, P. M.; OPPENHEIMER, N.; WANG, J. M.; LUND, F.

JOURNAL OF IMMUNOLOGY

Año: 2004 vol. 172 p. 1896 - 1906

0022-1767

Cyclic ADP ribose (cADPR) is a calcium-mobilizing metabolite that regulates intracellular calcium release and extracellularcalcium influx. Although the role of cADPR in modulating calcium mobilization has been extensively examined, its potential rolein regulating immunologic responses is less well understood. We previously reported that cADPR, produced by the ADP-ribosylcyclase, CD38, controls calcium influx and chemotaxis of murine neutrophils responding to fMLF, a peptide agonist for twochemoattractant receptor subtypes, formyl peptide receptor and formyl peptide receptor-like 1. In this study, we examine whethercADPR is required for chemotaxis of human monocytes and neutrophils to a diverse array of chemoattractants. We found thata cADPR antagonist and a CD38 substrate analogue inhibited the chemotaxis of human phagocytic cells to a number of formylpeptide receptor-like 1-specific ligands but had no effect on the chemotactic response of these cells to ligands selective for formylpeptide 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 chemokinesthat induce extracellular calcium influx in the apparent absence of significant intracellular calcium release. Thus, cADPR regulatescalcium signaling of a discrete subset of chemoattractant receptors expressed by human leukocytes. Since many of the chemoattractantreceptors regulated by cADPR bind to ligands that are associated with clinical pathology, cADPR and CD38 representnovel drug targets with potential application in chronic inflammatory and neurodegenerative disease.