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Department of Physiology and Pathology, University of Trieste, Trieste, Italy
Chloride ion efflux is an early event occurring after exposure of human neutrophils to several soluble agonists. Under these circumstances, a rapid and reversible fall in the high basal intracellular chloride (Cl–i) levels is observed. This event is thought to play a crucial role in the modulation of several critical neutrophil responses including activation and up-regulation of adhesion molecules, cell attachment and spreading, cytoplasmic alkalinization, and activation of the respiratory burst. At present, however, no data are available on chloride ion movements during neutrophil phagocytosis. In this study, we provide evidence that phagocytosis of Candida albicans opsonized with either whole serum, complement-derived opsonins, or purified human IgG elicits an early and long-lasting Cl– efflux accompanied by a marked, irreversible loss of Cl–i. Simultaneous assessment of Cl– efflux and phagocytosis in cytochalasin D-treated neutrophils indicated that Cl– efflux occurs without particle ingestion. These results suggest that engagement of immune receptors is sufficient to promote chloride ion movements. Several structurally unrelated chloride channel blockers inhibited phagocytosis-induced Cl– efflux as well as the release of azurophilic—but not specific—granules. It implicates that different neutrophil secretory compartments display distinct sensitivity to Cl–i modifications. Intriguingly, inhibitors of Cl– exchange inhibited cytosolic Ca2+ elevation, whereas Cl– efflux was not impaired in Ca2+-depleted neutrophils. We also show that Fc
R(s)- and CR3/CR1-mediated Cl– efflux appears to be dependent on protein tyrosine phosphorylation but independent of PI3K and phospholipase C activation.
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1 Address correspondence and reprint requests to Dr. Renzo Menegazzi, Department of Physiology and Pathology, University of Trieste, via A. Fleming, 22, Trieste, Italy. E-mail address: menegazz{at}units.it
2 Abbreviations used in this paper: Cl–i, intracellular chloride content; EA, [2,3-dichloro-4-(2-methylene-butyryl)phenoxy]acetic acid (ethacrynic acid); DIDS, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid; NPPB, 5-nitro-2-(3-phenylpropylamino)benzoic acid; NA, 2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid (niflumic acid); FLX, 3-p-trifluoromethylphenoxy-3-phenyl-N-methyl-propylamine hydrochloride (fluoxetine); 9-AC, anthracene-9-carboxylic acid; MA, (o-[3-hydroxymercuri-2-methoxy-propyl)carbamoyl] phenoxyacetic acid (mersalyl); CHC, 
-cyano-4-hydroxy-cinnamic acid; TB, trypan blue; HBS-BSA, HEPES-buffered saline containing 0.2% BSA; STZ, serum-treated zymosan; 5(6)-FAM-SE, 5-(and 6)-carboxyfluorescein succinimidyl ester; FCM, fluorescence flow cytometry; MPO, myeloperoxidase; LF, lactoferrin; HZ, hydrazide; TEM, transmission electron microscopy; TK, tyrosine kinase; Ptx, pertussis toxin; U73122, 1-(6-{[17
-3-methoxyoesta-1,3,5(10)-trien-17-yl]amino}hexyl)-1H-pyrrole-2,5-dione; U73343, 1-(6-{[17-3-methoxyoesta-1,3,5(10)-trien-17-yl]amino}hexyl)-pyrrolidine-2,5-dione; PLC, phospholipase C; DAG, diacylglycerol.
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