Laboratory of Molecular and Genetic Information, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Biochem Biophys Res Commun. 2019 Nov 5;519(2):220-226. doi: 10.1016/j.bbrc.2019.08.158. Epub 2019 Sep 4.
While most asthma can be treated with steroids, about 10%, called severe asthma, is refractory to steroids. It has recently been shown that in a subgroup of severe asthma cases, neutrophils that infiltrate into the airways play an important role in inflammation. However, the mechanisms underlying this increased neutrophil infiltration are not well understood. Here, using a mouse model of steroid-resistant neutrophilic inflammation, we show that mice deficient for the RNA-binding protein Mex-3B have significantly less neutrophil infiltration in the airways than wild-type mice. We further demonstrate that Mex-3B post-transcriptionally upregulates CXCL2, a chemokine that induces neutrophil chemotaxis and migration. Moreover, we show that treatment with either anti-CXCL2 antibody or anti-Mex-3B antisense oligonucleotide suppresses neutrophilic allergic airway inflammation. These results suggest that Mex-3B-mediated induction of CXCL2 is crucial for steroid-resistant neutrophilic allergic airway inflammation. Our findings suggest new strategies for therapeutic intervention in steroid-resistant severe asthma.
虽然大多数哮喘可以用类固醇治疗，但约 10%的哮喘，称为严重哮喘，对类固醇有抗药性。最近的研究表明，在严重哮喘的亚组中，浸润到气道中的中性粒细胞在炎症中起着重要作用。然而，这种中性粒细胞浸润增加的机制尚不清楚。在这里，我们使用一种对抗生素耐药的中性粒细胞炎症的小鼠模型，显示 RNA 结合蛋白 Mex-3B 缺失的小鼠在气道中的中性粒细胞浸润明显少于野生型小鼠。我们进一步证明 Mex-3B 通过转录后水平上调趋化因子 CXCL2，该趋化因子诱导中性粒细胞趋化和迁移。此外，我们还表明，用抗 CXCL2 抗体或抗 Mex-3B 反义寡核苷酸治疗可抑制中性粒细胞变应性气道炎症。这些结果表明，Mex-3B 介导的 CXCL2 诱导对于对抗生素耐药的中性粒细胞变应性气道炎症至关重要。我们的发现为治疗对抗生素耐药的严重哮喘提供了新的策略。
