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.
Highlights
Type I interferon (IFN-I) is a family of pleiotropic cytokines that modulate the innate and adaptive immunity and play a critical role in antiviral responses [1]
When mice were passively inoculated with trinitrophenyl (TNP)–specific immunoglobulin E (IgE) and TNP-conjugated bovine serum albumin (BSA), more severe hypothermia was observed in the Ifnar1−/− mice than in the wild-type (WT) mice (Fig 1A)
We here investigated the effect of type I interferon (IFN-I) on mast cell functions using Ifnar1−/− mice, and revealed that IFN-I has a critical role in mast cell homeostasis to limit mast cell–dependent anaphylaxis
Summary
Type I interferon (IFN-I) is a family of pleiotropic cytokines that modulate the innate and adaptive immunity and play a critical role in antiviral responses [1]. The IFN-I family consists of 13 IFN-α subtypes and IFN-β, IFN-β, IFN-κ, and IFN-ω, and others in some species [2,3]. All IFN-I molecules bind to a receptor consisting of type-I interferon (IFN-α/β) receptor (IFNAR) and IFNAR2, and the resulting ternary complex forms an active signaling receptor [4]. IFN-I interacts with IFNAR1 and IFNAR2 with different affinities, structural analyses combined with site-directed mutagenesis demonstrated that IFNAR1 is necessary for the signaling of IFN-I [2,5]. After IFN-I binds to the receptor, the Janus family kinases
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