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Mast cell desensitization inhibits calcium flux and aberrantly remodels actin
W.X. Gladys Ang, … , A. Wesley Burks, Soman N. Abraham
W.X. Gladys Ang, … , A. Wesley Burks, Soman N. Abraham
Published September 26, 2016
Citation Information: J Clin Invest. 2016;126(11):4103-4118. https://doi.org/10.1172/JCI87492.
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Research Article Immunology Article has an altmetric score of 43

Mast cell desensitization inhibits calcium flux and aberrantly remodels actin

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Abstract

Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses.

Authors

W.X. Gladys Ang, Alison M. Church, Mike Kulis, Hae Woong Choi, A. Wesley Burks, Soman N. Abraham

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Figure 9

Manipulation of the actin cytoskeleton reverses desensitization in vitro and in vivo.

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Manipulation of the actin cytoskeleton reverses desensitization in vitro...
(A) Control (C481S-Ag) or desensitized (C481S-DS) BMMCs were treated with SptPC481S-TAT (C481S-Ag, C481S-DS) or buffer (control Ag, control DS/Ag) for 30 minutes before being loaded with Fluo-4. After measurement of baseline fluorescence for 2 minutes, cells were activated with 10 ng/ml Ag and ionomycin. A representative graph is shown. AUC was averaged from 4–5 independent experiments. (B) Control (IgE/Ag, buffer, and ionomycin) or desensitized (DS/Ag) BMMCs were treated with 10 μg SptPC481S-TAT (C481S) or untreated before challenge with Ag, buffer, or ionomycin for β-hexosaminidase assay. Data are representative of at least 3 independent experiments. (C) IgE-sensitized mice were orally desensitized (DS, DS-C481S) or given PBS (Ag, Ag-C481S). Mice were then injected with 50 μg SptPC481S-TAT (Ag-C481S, DS-C481S) or equal volume PBS (Ag, DS). One hour later, mice were challenged i.p. with 500 μg Ag. Rectal temperatures were measured every 15 minutes for 30 minutes. Results were pooled from 2 independent experiments (n = 10). Data were analyzed via 2-way ANOVA (A and B) and repeated-measures ANOVA (C). Data represent SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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