Abstract
Mast cells represent a crucial cell type in host defense; however, maladaptive responses are contributing factors in the pathogenesis of allergic diseases. Previous work in our laboratory has shown that exposure to silver nanoparticles (AgNPs) results in mast cell degranulation via a non-immunoglobulin E (IgE) mechanism. In this study, we utilized a systems biology approach to identify novel genetic factors playing a role in AgNP-induced mast cell degranulation compared to the classical activation by antigen-mediated FcεRI crosslinking. Mast cell degranulation was assessed in bone marrow-derived mast cells isolated from 23 strains of mice following exposure to AgNPs or FcεRI crosslinking with dinitrophenyl (DNP). Utilizing strain-dependent mast cell degranulation, an association mapping study identified 3 chromosomal regions that were significantly associated with mast cell degranulation by AgNP and one non-overlapping region associated with DNP-mediated degranulation. Two of the AgNP-associated regions correspond to genes previously reported to be associated with allergic disorders (Trac2 on chromosome 1 and Traf6 on chromosome 2) and an uncharacterized gene identified on chromosome 1 (Fam126b). In conjunction, RNA-sequencing performed on mast cells from the high and low responder strains revealed 3754 and 34 differentially expressed genes that were unique to DNP and AgNP exposures, respectively. Select candidate genes include Ptger4, a gene encoding a G-protein coupled receptor in addition to a multifunctional adaptor protein, Txnip, that may be driving mast cell degranulation by AgNP. Taken together, we identified novel genes that have not been previously shown to play a role in nanoparticle-mediated mast cell activation. With further functional evaluation in the future, these genes may be potential therapeutic targets in the treatment of non-IgE mediated mast cell-linked disorders.
Highlights
In the last decade, development of new nanotechnologies has contributed to the advancement of many fields
Understanding the role of AgNP exposure in immunomodulation is critical for evaluating engineered nanomaterials (ENMs) safety for consumer health, which is especially concerning for the population susceptible to mast cell mediated-diseases such as asthma, allergic dermatitis and hyperactive mast cell activation disorders [12,13,14]
Genetic effects of mast cell degranulation caused by silver nanoparticles (AgNP) or FcεRI crosslinking by dinitrophenyl (DNP)
Summary
Development of new nanotechnologies has contributed to the advancement of many fields. A crucial cell type involved in allergic inflammation, have been shown to be activated in response to ENM exposures [5]. Exposure to a variety of physicochemically distinct ENMs including carbon-based and metal-based nanoparticles induce mast cell degranulation in vivo and in vitro [6,7,8,9]. We demonstrated a robust mast cell degranulation response following silver nanoparticle (AgNP) exposure, which was dependent on physicochemical properties such a size, shape and surface chemistry [10, 11]. Understanding the role of AgNP exposure in immunomodulation is critical for evaluating ENM safety for consumer health, which is especially concerning for the population susceptible to mast cell mediated-diseases such as asthma, allergic dermatitis and hyperactive mast cell activation disorders [12,13,14]
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