title: Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor.
abstract: Engineered nanomaterial (ENM)-mediated toxicity often involves triggering immune responses. Mast cells can regulate both innate and adaptive immune responses and are key effectors in allergic diseases and inflammation. Silver nanoparticles (AgNPs) are one of the most prevalent nanomaterials used in consumer products due to their antimicrobial properties. We have previously shown that AgNPs induce mast cell degranulation that was dependent on nanoparticle physicochemical properties. Furthermore, we identified a role for scavenger receptor B1 (SR-B1) in AgNP-mediated mast cell degranulation. However, it is completely unknown how SR-B1 mediates mast cell degranulation and the intracellular signaling pathways involved. In the current study, we hypothesized that SR-B1 interaction with AgNPs directs mast cell degranulation through activation of signal transduction pathways that culminate in an increase in intracellular calcium signal leading to mast cell degranulation. For these studies, we utilized bone marrow-derived mast cells (BMMC) isolated from C57Bl/6 mice and RBL-2H3 cells (rat basophilic leukemia cell line). Our data support our hypothesis and show that AgNP-directed mast cell degranulation involves activation of PI3K, PLCγ and an increase in intracellular calcium levels. Moreover, we found that influx of extracellular calcium is required for the cells to degranulate in response to AgNP exposure and is mediated at least partially via the CRAC channels. Taken together, our results provide new insights into AgNP-induced mast cell activation that are key for designing novel ENMs that are devoid of immune system activation.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Nasser B
authors.initials: NB
authors.lastname: Alsaleh
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Indushekhar
authors.initials: I
authors.lastname: Persaud
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D015550:Cell Degranulation / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000276:immunology; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis; D012834:Silver / Q000008:administration & dosage
chemical_list: D017455:Receptors, IgE; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D012834:Silver; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium