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- Title
Type I interferon limits mast cell–mediated anaphylaxis by controlling secretory granule homeostasis.
- Authors
Kobayashi, Toshihiko; Shimabukuro-Demoto, Shiho; Tsutsui, Hidemitsu; Toyama-Sorimachi, Noriko
- Abstract
Type I interferon (IFN-I) is a family of multifunctional cytokines that modulate the innate and adaptive immunity and are used to treat mastocytosis. Although IFN-I is known to suppress mast cell function, including histamine release, the mechanisms behind its effects on mast cells have been poorly understood. We here investigated IFN-I's action on mast cells using interferon-α/β receptor subunit 1 (Ifnar1)-deficient mice, which lack a functional IFN-I receptor complex, and revealed that IFN-I in the steady state is critical for mast cell homeostasis, the disruption of which is centrally involved in systemic anaphylaxis. Ifnar1-deficient mice showed exacerbated systemic anaphylaxis after sensitization, which was associated with increased histamine in the circulation, even though the mast cell numbers and high affinity immunoglobulin E receptor (FcεRI) expression levels were similar between Ifnar1-deficient and wild-type (WT) mice. Ifnar1-deficient mast cells showed increased secretory granule synthesis and exocytosis, which probably involved the increased transcription of Tfeb. Signal transducer and activator of transcription 1(Stat1) and Stat2 were unexpectedly insufficient to mediate these IFN-I functions, and instead, Stat3 played a critical role in a redundant manner with Stat1. Our findings revealed a novel regulation mechanism of mast cell homeostasis, in which IFN-I controls lysosome-related organelle biogenesis. This study reveals a novel role for type I interferon in mast cell homeostasis; spontaneous type I interferon signaling regulates the biogenesis of secretory granules and maturation of mast cells via STAT1 and STAT3, and limits the onset of systemic anaphylaxis.
- Subjects
TYPE I interferons; INTERFERON receptors; SECRETORY granules; IMMUNOGLOBULIN E; MAST cells; IMMUNOGLOBULIN receptors; ANAPHYLAXIS
- Publication
PLoS Biology, 2019, Vol 17, Issue 11, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000530