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Role of Intracellular Chloride in the Reversible Activation of Neutrophil ß₂ Integrins: A Lesson from TNF Stimulation¹

Department of Physiology and Pathology, University of Trieste, Trieste, Italy

The process of ß₂ integrin activation, which enhances the interaction of these heterodimers with ligands, plays a crucial role in the adherence-dependent neutrophilic polymorphonuclear leukocytes’ (PMN) responses to TNF. Our previous observation, showing that a marked decrease of the high basal Cl^- content (Cl^-_i) is an essential step in the TNF-induced activation of PMN, stimulated this study, which investigates the role of alterations of Cl^-_i in the activation of ß₂ integrins triggered by TNF. Here we show that TNF enhances the expression of activation-specific neoepitopes of ß₂ integrins, namely, epitope 24, a unique epitope present on all three leukocyte integrin subunits, and epitope CBRM1/5, localized to the I domain on the -chain of Mac-1 (CD11bCD18). Moreover, we demonstrate that the conformational changes underlying the expression of the neoepitopes are dependent on a drop in Cl^-_i because 1) inhibition of Cl^-_i decrease is invariably accompanied by inhibition of ß₂ integrin activation, 2) Cl^-_i decrease induced by means other than agonist stimulation, i.e., by placing PMN in Cl^--free buffers, activates ß₂ integrins, and 3) restoration of the original Cl^-_i levels is accompanied by deactivation of ß₂ integrins. We also show that Cl^-_i decrease is required for TNF-induced cytoplasmic alkalinization, but such a rise in pH_i does not seem to be relevant for ß₂ integrin activation. The results of our study emphasize the role of Cl^- as a new PMN "second messenger."

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