肥大细胞通过前列腺素E2驱动的可溶性ST2控制肺2型炎症
2024/06/26
摘要
重度哮喘和鼻窦疾病是2型炎症（T2I）的后果，由白细胞介素（IL）-33信号通过其膜结合受体ST2介导。可溶性ST2降低可用的IL-33并限制T2I，但对其调节知之甚少。我们证明前列腺素E2（PGE2）驱动sST2的产生以限制肺T2I的特征。PGE2缺乏的小鼠表现出sST2减少。在患有严重呼吸道T2I的人类中，尿PGE2代谢产物与血清sST2相关。在小鼠中，PGE2增强肥大细胞（MC）分泌sST2。缺乏MCs、MCs表达ST2或MCs表达E前列腺素（EP）2受体的小鼠表现出sST2肺浓度降低和T2I增强。重组sST2将缺乏MCs表达PGE2或ST2的小鼠的T2I降低到对照水平。PGE2缺乏也逆转了MCs缺乏ST2表达的小鼠的高炎症表型。因此，PGE2通过MC衍生的sST2抑制T2I，解释了在低PGE2状态下观察到的严重T2I。
Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2
Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F Dwyer, Joshua A Boyce
Abstract
Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.
重度哮喘和鼻窦疾病是2型炎症（T2I）的后果，由白细胞介素（IL）-33信号通过其膜结合受体ST2介导。可溶性ST2降低可用的IL-33并限制T2I，但对其调节知之甚少。我们证明前列腺素E2（PGE2）驱动sST2的产生以限制肺T2I的特征。PGE2缺乏的小鼠表现出sST2减少。在患有严重呼吸道T2I的人类中，尿PGE2代谢产物与血清sST2相关。在小鼠中，PGE2增强肥大细胞（MC）分泌sST2。缺乏MCs、MCs表达ST2或MCs表达E前列腺素（EP）2受体的小鼠表现出sST2肺浓度降低和T2I增强。重组sST2将缺乏MCs表达PGE2或ST2的小鼠的T2I降低到对照水平。PGE2缺乏也逆转了MCs缺乏ST2表达的小鼠的高炎症表型。因此，PGE2通过MC衍生的sST2抑制T2I，解释了在低PGE2状态下观察到的严重T2I。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Immunity. 2024 May 24:S1074-7613(24)00254-1. doi: 10.1016/j.immuni.2024.05.003.)
(Immunity. 2024 May 24:S1074-7613(24)00254-1. doi: 10.1016/j.immuni.2024.05.003.)
Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2
Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F Dwyer, Joshua A Boyce
Abstract
Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.
上一篇：
Vandetanib 作为治疗哮喘的前瞻性抗炎和抗收缩剂
下一篇：
通过孟德尔随机化，蛋白质组学分析揭示了儿童哮喘的潜在治疗靶点
