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This Article Full Text (PDF) All Versions of this Article: jimmunol.0804061v1 183/2/1413    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Pushparaj, P. N. Articles by Melendez, A. J. PubMed PubMed Citation Articles by Pushparaj, P. N. Articles by Melendez, A. J.

VAMP8 Is Essential in Anaphylatoxin-Induced Degranulation, TNF- Secretion, Peritonitis, and Systemic Inflammation

Peter N. Pushparaj^*,, Hwee Kee Tay^*,, Cheng-Chun Wang, Wanjin Hong and Alirio J. Melendez^*,,1

*Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Division of Immunology, Infection and Inflammation, Faculty of Medicine, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, Scotland; and Institute of Molecular and Cell Biology, Singapore, Republic of Singapore

VAMP8, a member of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) family of fusion proteins, initially characterized in endosomal and endosomal-lysosomal fusion, may also function in regulated exocytosis. VAMP8 physiological function in inflammation has not been elucidated. In this paper, we show that deficiency of VAMP8 protects mice from anaphylatoxin (C5a)-induced neutropenia, peritonitis, and systemic inflammation. We show that, in vivo, VAMP8 deletion inhibits neutropenia and phagocyte recruitment. We also show that in macrophages, VAMP8 localizes on secretory granules and degranulation is inhibited in VAMP8-deficient macrophages. Moreover, VAMP8^–/– mice show reduced systemic inflammation with inhibition of serum TNF- levels, whereas IL-1β, IL-6, and MIP1 release are not affected. In wild-type macrophages, TNF- colocalizes with VAMP8-positive vesicles, and in VAMP8-deficient macrophages, the TNF- release is inhibited. Furthermore, VAMP8 regulates the release of TNF- and β-hexosaminidase triggered by fMLP, and VAMP8^–/– mice are protected from fMLP-induced peritonitis. These data demonstrate that the VAMP8 vesicle-associated-SNARE is required for the proper trafficking of secretory lysosomal granules for exocytosis in macrophages and for the release of the potent proinflammatory cytokine, TNF-.

Address correspondence and reprint requests to Dr. Alirio J. Melendez, Division of Immunology, Infection and Inflammation, Faculty of Medicine, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, U.K. E-mail address: a.melendez-romero{at}clinmed.gla.ac.uk