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RNA结合蛋白RBM3通过CysLT1R部分抑制肺固有淋巴细胞活化和炎症

2022/08/19

   摘要
   固有淋巴细胞(ILC)通过产生细胞因子促进哮喘患者的肺部炎症。RNA结合蛋白(RBPs)是关键的转录后调节因子,但对其在ILC生物学中的作用知之甚少。在这里,我们证明RNA结合基序3(RBM3)在肺ILC中高度表达,并由alarmins TSLP和IL-33进一步诱导。RBM3-/-和RBM3-/-Rag2-/-暴露于哮喘相关交链孢变应原的小鼠出现增强的嗜酸性肺炎和ILC激活。体内外IL-33刺激研究表明,RBM3抑制肺ILC反应。此外,来自骨髓嵌合体小鼠的Rbm3-/-ILC显示ILC细胞因子产生增加,表明Rbm3具有ILC固有的抑制功能。Rbm3-/-肺ILC的RNA测序显示2/17型细胞因子和半胱氨酸白三烯1受体(CysLT1R)的表达增加。最后,Rbm3-/-Cyslt1r-/-小鼠在ST2+IL-17+ILCs的积累方面表现出对CysLT1R的依赖性。因此,在部分依赖CysLT1R的过敏原诱导的2型炎症期间,RBM3内在地调节肺ILC。

 
(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)
(Nat Commun. 2022 Jul 30;13(1):4435. doi: 10.1038/s41467-022-32176-5.)

 
 
 
RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R
 
Jana H Badrani, Allyssa N Strohm, Lee Lacasa, Blake Civello, Kellen Cavagnero, Yung-An Haung, Michael Amadeo, Luay H Naji, Sean J Lund, Anthea Leng, Hyojoung Kim, Rachel E Baum, Naseem Khorram, Monalisa Mondal, Grégory Seumois, Julie Pilotte, Peter W Vanderklish, Heather M McGee, Taylor A Doherty
 
Abstract
Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.




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