Type I interferon limits mast cell–mediated anaphylaxis by controlling secretory granule homeostasis
Open Access
- 15 November 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 17 (11), e3000530
- https://doi.org/10.1371/journal.pbio.3000530
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.Keywords
Funding Information
- The Ministry of Education, Science, Sports and Culture of Japan (17H04070)
- The Ministry of Education, Science, Sports and Culture of Japan (18K07056)
- National Center for Global Health and Medicine (23S001)
This publication has 43 references indexed in Scilit:
- Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1Nature Immunology, 2013
- TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loopNature, 2013
- The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome HomeostasisScience Signaling, 2012
- Constitutive Type I Interferon Modulates Homeostatic Balance through Tonic SignalingImmunity, 2012
- A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEBThe EMBO Journal, 2012
- A Gene Network Regulating Lysosomal Biogenesis and FunctionScience, 2009
- Role of STAT3 in Type I Interferon ResponsesOnline Journal of Public Health Informatics, 2006
- Treatment of adult systemic mastocytosis with interferon‐α: results of a multicentre phase II trial on 20 patientsBritish Journal of Haematology, 2002
- Systemic MastocytosisThe New England Journal of Medicine, 1992
- Response to Interferon Alfa-2b in a Patient with Systemic MastocytosisThe New England Journal of Medicine, 1992