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

Journal of Leukocyte Biology

Susanna Mandruzzato⁴  Gaia Barisione¹  Luciano Ottonello²  Ottavia Barbieri³  Rita Rotondo⁵  Franco Dallegri²  Maria Bertolotto²  Simonetta Astigiano¹  Vincenzo Bronte–⁶  Silvano Ferrini and¹ 

[1] Department of Translational Oncology, National Institute for Cancer Research, Genova, Italy; Internal Medicine, University of Genova, Italy;Departments of Experimental Medicine and Department of Translational Oncology, National Institute for Cancer Research, Genova, Italy;Department of Oncological and Surgical Sciences, University of Padova, Italy;Departments of Experimental Medicine and  Internal Medicine, University of Genova, Italy;–University Hospital and Department of Pathology, Verona, Italy  Internal Medicine, University of Genova, Italy;

关键词: granulocytes;    T cell proliferation;    arginase;    granules;   

DOI  :  10.1189/jlb.1109737

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown