Type I interferon limits mast cell-mediated anaphylaxis by controlling secretory granule homeostasis

PLoS Biol. 2019 Nov 15;17(11):e3000530. doi: 10.1371/journal.pbio.3000530. eCollection 2019 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylaxis / immunology*
  • Animals
  • Cells, Cultured
  • Histamine / blood
  • Homeostasis
  • Interferon Type I / physiology*
  • Mast Cells / immunology*
  • Mice
  • Receptor, Interferon alpha-beta / genetics
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / physiology
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / physiology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / physiology
  • Secretory Vesicles / metabolism*
  • Signal Transduction

Substances

  • Interferon Type I
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat2 protein, mouse
  • Stat3 protein, mouse
  • Receptor, Interferon alpha-beta
  • Histamine

Grants and funding

This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (http://www.mext.go.jp/en/) (for NT-S, 17H04070; for TK, 18K07056) and by a grant from the National Center for Global Health and Medicine (https://www.ncgm.go.jp/en/index.html) (for NT-S, 23S001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.