An Essential Role of STIM1, Orai1, and S100A8–A9 Proteins for Ca2+ Signaling and FcγR-Mediated Phagosomal Oxidative Activity
Autor: | Sabrina Bréchard, Eric Tschirhart, Natacha Steinckwich, Véronique Schenten, Chantal Melchior |
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Rok vydání: | 2011 |
Předmět: |
Intracellular Fluid
Thapsigargin ORAI1 Protein Neutrophils Phagocytosis media_common.quotation_subject Immunology HL-60 Cells Biology chemistry.chemical_compound BAPTA Phagosomes Extracellular Calgranulin B Humans Immunology and Allergy Calgranulin A Calcium Signaling Stromal Interaction Molecule 1 Internalization Cells Cultured Phagosome media_common ORAI1 Receptors IgG Membrane Proteins Extracellular Fluid Neoplasm Proteins Cell biology chemistry Calcium Channels Signal transduction Reactive Oxygen Species |
Zdroj: | The Journal of Immunology. 186:2182-2191 |
ISSN: | 1550-6606 0022-1767 |
Popis: | Phagocytosis is a process of innate immunity that allows for the enclosure of pathogens within the phagosome and their subsequent destruction through the production of reactive oxygen species (ROS). Although these processes have been associated with increases of intracellular Ca2+ concentrations, the mechanisms by which Ca2+ could regulate the different phases of phagocytosis remain unknown. The aim of this study was to investigate the Ca2+ signaling pathways involved in the regulation of FcγRs-induced phagocytosis. Our work focuses on IgG-opsonized zymosan internalization and phagosomal ROS production in DMSO-differentiated HL-60 cells and neutrophils. We found that chelation of intracellular Ca2+ by BAPTA or emptying of the intracellular Ca2+ store by thapsigargin reduced the efficiency of zymosan internalization. Using an small interfering RNA strategy, our data establish that the observed Ca2+ release occurs through two isoforms of inositol 1,4,5-triphosphate receptors, ITPR1 and ITPR3. In addition, we provide evidence that phagosomal ROS production is dependent on extracellular Ca2+ entry. We demonstrate that the observed Ca2+ influx is supported by ORAI calcium release-activated calcium modulator 1 (Orai1) and stromal interaction molecule 1 (STIM1). This result suggests that extracellular Ca2+ entry, which is required for ROS production, is mediated by a store-operated Ca2+ mechanism. Finally, our data identify the complex formed by S100A8 and S100A9 (S100 calcium-binding protein A8 and A9 complex), two Ca2+-binding proteins, as the site of interplay between extracellular Ca2+ entry and intraphagosomal ROS production. Thus, we demonstrate that FcγR-mediated phagocytosis requires intracellular Ca2+ store depletion for the internalization phase. Then phagosomal ROS production requires extracellular Ca2+ entry mediated by Orai1/STIM1 and relayed by S100A8–A9 as Ca2+ sensor. |
Databáze: | OpenAIRE |
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