Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit t lymphocyte proliferation

Rita Rotondo, Maria Bertolotto, Gaia Barisione, Simonetta Astigiano, Susanna Mandruzzato, Luciano Ottonello, Franco Dallegri, Vincenzo Bronte, Silvano Ferrini, Ottavia Barbieri

Research output: Contribution to journalArticle

Abstract

ARG1, expressed by human PMNs, inhibits T cell proliferation by depleting extracellular L-arginine. Here, we report that ARG1, released from gelatinase granules by PMNs, is inactive at physiological pH unless activated by factor(s) stored in azurophil granules. Whereas ARG1 exocytosis was induced by TNF-α or ionomycin, only the latter mediated the release of both granules, resulting in extracellular ARG enzyme activity at physiological pH. Furthermore, after fractionation of the different classes of granules, only the mixture of gelatinase and azurophil granules resulted in ARG1 activity at physiological pH. The use of protease inhibitors indicated the involvement of a PMSF- and leupeptin-susceptible serine protease in ARG1 processing and activation. Finally, the supernatant of viable PMNs undergoing frustrated phagocytosis, which mediates gelatinase and azurophil granule release, inhibited T cell proliferation through ARG-dependent mechanisms. In vivo, high ARG1 concentrations and increased ARG enzyme activity, sufficient to inhibit T cell proliferation, were observed in synovial fluids from RA. These findings suggest that PMNs, recruited at sites of immune complex deposition, induce ARG1-dependent immune suppression through concomitant exocytosis of gelatinase and azurophil granules.

Original languageEnglish
Pages (from-to)721-727
Number of pages7
JournalJournal of Leukocyte Biology
Volume89
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • Arginase
  • Granules
  • Granulocytes
  • T cell proliferation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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    Rotondo, R., Bertolotto, M., Barisione, G., Astigiano, S., Mandruzzato, S., Ottonello, L., Dallegri, F., Bronte, V., Ferrini, S., & Barbieri, O. (2011). Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit t lymphocyte proliferation. Journal of Leukocyte Biology, 89(5), 721-727. https://doi.org/10.1189/jlb.1109737