肥大细胞通过前列腺素E2驱动可溶性ST2控制肺部2型炎症
2025/01/06
本文亮点
·在2型肺部炎症中，PGE2是升高肺内sST2水平所必需的
·上皮内肥大细胞是PGE2驱动的肺sST2产生的主要来源
·肥大细胞来源的sST2缺乏会加重2型肺部炎症
·PGE2可以改变肥大细胞转录并促进短Il1rl1表达
总结
2型炎症可导致重度哮喘和鼻窦疾病，并且由IL-33信号通过其膜结合受体ST2介导。可溶性ST2（sST2）可降低IL-33的作用并限制2型炎症，但目前对其调控机制研究较少。本研究阐明了前列腺素E2（PGE2）驱动产生sST2可限制肺部2型炎症。PGE2缺陷小鼠表现出sST2减少。在患有重度呼吸道2型炎症的患者中，尿液PGE2代谢产物与血清sST2呈正相关。在小鼠中，PGE2促进肥大细胞分泌sST2。在缺乏肥大细胞、表达ST2的肥大细胞或表达EP2受体肥大细胞的小鼠中表现出肺sST2浓度降低和2型炎症增强。在缺乏PGE2或肥大细胞表达ST2的小鼠中，重组sST2减少2型炎症到控制水平。PGE2缺乏还可逆转缺乏ST2表达肥大细胞的小鼠高炎症表型。因此，PGE2通过肥大细胞产生sST2抑制2型炎症，这可以解释在低PGE2状态下观察到的严重2型炎症状态。
Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2
Immunity. 2024 Jun 11;57(6):1274-1288.e6..
Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum 1, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F Dwyer, Joshua A Boyce
Highlights
•PGE2 is necessary to elevate sST2 levels in the lung with type 2 lung inflammation
•Intraepithelial mast cells are the principal source of PGE2-driven lung sST2 production
•Deficiency of mast-cell-derived sST2 exaggerates type 2 lung inflammation
•PGE2 alters the mast cell transcriptome and promotes short Il1rl1 expression
Summary
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.
·在2型肺部炎症中，PGE2是升高肺内sST2水平所必需的
·上皮内肥大细胞是PGE2驱动的肺sST2产生的主要来源
·肥大细胞来源的sST2缺乏会加重2型肺部炎症
·PGE2可以改变肥大细胞转录并促进短Il1rl1表达
总结
2型炎症可导致重度哮喘和鼻窦疾病，并且由IL-33信号通过其膜结合受体ST2介导。可溶性ST2（sST2）可降低IL-33的作用并限制2型炎症，但目前对其调控机制研究较少。本研究阐明了前列腺素E2（PGE2）驱动产生sST2可限制肺部2型炎症。PGE2缺陷小鼠表现出sST2减少。在患有重度呼吸道2型炎症的患者中，尿液PGE2代谢产物与血清sST2呈正相关。在小鼠中，PGE2促进肥大细胞分泌sST2。在缺乏肥大细胞、表达ST2的肥大细胞或表达EP2受体肥大细胞的小鼠中表现出肺sST2浓度降低和2型炎症增强。在缺乏PGE2或肥大细胞表达ST2的小鼠中，重组sST2减少2型炎症到控制水平。PGE2缺乏还可逆转缺乏ST2表达肥大细胞的小鼠高炎症表型。因此，PGE2通过肥大细胞产生sST2抑制2型炎症，这可以解释在低PGE2状态下观察到的严重2型炎症状态。
(四川大学华西医院呼吸与危重症医学科 林红霞1 王霁1 王刚1 译)
(Immunity. 2024 Jun 11;57(6):1274-1288.e6..)
(Immunity. 2024 Jun 11;57(6):1274-1288.e6..)
Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2
Immunity. 2024 Jun 11;57(6):1274-1288.e6..
Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum 1, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F Dwyer, Joshua A Boyce
Highlights
•PGE2 is necessary to elevate sST2 levels in the lung with type 2 lung inflammation
•Intraepithelial mast cells are the principal source of PGE2-driven lung sST2 production
•Deficiency of mast-cell-derived sST2 exaggerates type 2 lung inflammation
•PGE2 alters the mast cell transcriptome and promotes short Il1rl1 expression
Summary
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.
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