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Type I interferon limits mast cell-mediated anaphylaxis by controlling secretory granule homeostasis.
PLOS Biology ( IF 7.8 ) Pub Date : 2019-11-15 , DOI: 10.1371/journal.pbio.3000530
Toshihiko Kobayashi 1 , Shiho Shimabukuro-Demoto 1 , Hidemitsu Tsutsui 1 , Noriko Toyama-Sorimachi 1
Affiliation  

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.

中文翻译:

I型干扰素通过控制分泌颗粒的稳态来限制肥大细胞介导的过敏反应。

I型干扰素(IFN-I)是一类多功能细胞因子,可调节先天免疫和适应性免疫,可用于治疗肥大细胞增多症。尽管已知IFN-1抑制肥大细胞功能,包括组胺释放,但其对肥大细胞作用的机制尚不清楚。我们在这里使用缺乏功能性IFN-I受体复合物的干扰素-α/β受体亚基1(Ifnar1)缺陷小鼠调查了IFN-I对肥大细胞的作用,并揭示了稳定状态下的IFN-I对于肥大至关重要细胞稳态,其破坏主要涉及全身性过敏反应。Ifnar1缺陷型小鼠在致敏后显示出加剧的全身过敏反应,这与循环中组胺的增加有关,即使在Ifnar1缺陷小鼠和野生型(WT)小鼠之间,肥大细胞数量和高亲和力免疫球蛋白E受体(FcεRI)表达水平相似。Ifnar1缺乏的肥大细胞显示出增加的分泌性颗粒合成和胞吐作用,这可能与Tfeb的转录增加有关。信号转导和转录激活因子1(Stat1)和Stat2出乎意料地不足以介导这些IFN-I功能,取而代之的是,Stat3与Stat1冗余地起着关键作用。我们的发现揭示了肥大细胞稳态的一种新型调节机制,其中IFN-1控制了溶酶体相关细胞器的生物发生。这可能与Tfeb转录的增加有关。信号转导和转录激活因子1(Stat1)和Stat2出乎意料地不足以介导这些IFN-I功能,取而代之的是,Stat3与Stat1冗余地起着关键作用。我们的发现揭示了肥大细胞稳态的一种新型调节机制,其中IFN-1控制了溶酶体相关细胞器的生物发生。这可能与Tfeb转录的增加有关。信号转导和转录激活因子1(Stat1)和Stat2出乎意料地不足以介导这些IFN-I功能,取而代之的是,Stat3与Stat1冗余地起着关键作用。我们的发现揭示了肥大细胞稳态的一种新型调节机制,其中IFN-1控制了溶酶体相关细胞器的生物发生。
更新日期:2019-12-03
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