Expression of Antizyme Inhibitor 2 in Mast Cells and Role of Polyamines as Selective Regulators of Serotonin Secretion

Abstract

BackgroundUpon IgE-mediated activation, mast cells (MC) exocytose their cytoplasmic secretory granules and release a variety of bioactive substances that trigger inflammatory responses. Polyamines mediate numerous cellular and physiological functions. We report here that MCs express antizyme inhibitor 2 (AZIN2), an activator of polyamine biosynthesis, previously reported to be exclusively expressed in the brain and testis. We have investigated the intracellular localization of AZIN2 both in resting and activated MCs. In addition, we have examined the functional role of polyamines, downstream effectors of AZIN2, as potential regulators of MC activity.Methodology/Principal FindingsImmunostainings show that AZIN2 is expressed in primary and neoplastic human and rodent MCs. We demonstrate that AZIN2 localizes in the Vamp-8 positive, serotonin-containing subset of MC granules, but not in tryptase-containing granules, as revealed by double immunofluorescence stainings. Furthermore, activation of MCs induces rapid upregulation of AZIN2 expression and its redistribution, suggesting a role for AZIN2 in secretory granule exocytosis. We also demonstrate that release of serotonin from activated MCs is polyamine-dependent whereas release of histamine and β-hexosaminidase is not, indicating a granule subtype-specific function for polyamines.Conclusions/SignificanceThe study reports for the first time the expression of AZIN2 outside the brain and testis, and demonstrates the intracellular localization of endogenous AZIN2 in MCs. The granule subtype-specific expression and its induction after MC activation suggest a role for AZIN2 as a local, in situ regulator of polyamine biosynthesis in association with serotonin-containing granules of MCs. Furthermore, our data indicates a novel function for polyamines as selective regulators of serotonin release from MCs.

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

“…3 Mast cells are a local source of serotonin, mediating edema formation and modulating vascular tone. 46 However, it is very unlikely that SSRI treatment also depletes mast cell serotonin, because mast cells synthesize serotonin in their cytoplasm with TPH1, which means that interrupting serotonin uptake with SSRI would not reduce intracellular serotonin contents. 14 The same reasoning applies to endothelial cells and monocytes/macrophages.…”

Polyphosphate Is a Novel Pro-inflammatory Regulator of Mast Cells and Is Located in Acidocalcisomes

“…When activated, mast cells secrete their cytoplasmic granules to the media, releasing a wide selection of cell modulators such as heparin, histamine, serotonin, neutral proteases, growth factors, and proinflammatory cytokines (21). These secretory granules are distributed in different subsets wherein histamine and serotonin are localized separately (22,23). Interestingly, mast cell lysates have been shown to have a pro-coagulant effect (24), and chronic urticaria, which is an autoimmune disease associated with the presence of histamine-releasing autoantibodies against the high affinity IgE receptor of mast cells and basophils, is associated with activation of blood coagulation (25).…”

Polyamine-independent Expression of Caenorhabditis elegans Antizyme

“…Here it is important to note that the putative C. elegans AZI shows higher homologies to the mammalian ODC paralogue also termed antizyme inhibitor AZI-two than toward the mammalian AZI-one (35). AZI-two expression has been found in testis and brain and more recently also in secretory tissues and other cell types (44,45). The physiological role of AZI-two is mostly unknown and a different way of regulating antizymes by diverging antizyme inhibitors could be possible (46).…”