Abstract
Mouse IgE and mast cell (MC) functions have been studied primarily using inbred strains. Here, we (a) identified effects of genetic background on mouse IgE and MC phenotypes, (b) defined the suitability of various strains for studying IgE and MC functions, and (c) began to study potentially novel genes involved in such functions. We screened 47 Collaborative Cross (CC) strains, as well as C57BL/6J and BALB/cJ mice, for strength of passive cutaneous anaphylaxis (PCA) and responses to the intestinal parasite Strongyloides venezuelensis (S.v.). CC mice exhibited a diversity in PCA strength and S.v. responses. Among strains tested, C57BL/6J and CC027 mice showed, respectively, moderate and uniquely potent MC activity. Quantitative trait locus analysis and RNA sequencing of BM-derived cultured MCs (BMCMCs) from CC027 mice suggested Sp140 as a candidate gene for MC activation. siRNA-mediated knock-down of Sp140 in BMCMCs decreased IgE-dependent histamine release and cytokine production. Our results demonstrated marked variations in IgE and MC activity in vivo, and in responses to S.v., across CC strains. C57BL/6J and CC027 represent useful models for studying MC functions. Additionally, we identified Sp140 as a gene that contributes to IgE-dependent MC activation.
Highlights
Mast cells (MCs) are of hematopoietic origin but reside in almost all vascularized tissues [1, 2]
We found 13 SNPs on Sp140 mRNA expressed in CC027 BM-derived cultured MCs (BMCMCs), of which 10 were already reported, including 2 NOD/ShiLtJ strain–specific missense SNPs shown in the Sanger database (Supplemental Table 7)
To examine the extent to which Sp140 is involved in IgE-dependent MC activation, we introduced an Sp140-specific siRNA into BMCMCs derived from C57BL/6J mice
Summary
Mast cells (MCs) are of hematopoietic origin but reside in almost all vascularized tissues [1, 2]. MCs play a pivotal role in type-2 inflammation [1, 2] and, in concert with IgE, help to protect mice from animal venoms [3], infections with Staphylococcus aureus [4], and infections with certain parasites [5]. MCs have been implicated in diseases not typically associated with type-2 immunity, including autoimmunity [7, 8] and cancer [9, 10]. Elucidating how MC phenotypes and functions can vary in different genetic backgrounds is critical in efforts to understand the potential roles of MCs in health and disease
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