Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice
Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice
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DOI：
10.1172/jci.insight.123578
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发表时间：
2018-11-02
期刊：
影响因子：
8
通讯作者：
Bhattacharya, Mallar
中科院分区：
文献类型：
--
作者：
Fong, Valerie;Hsu, Austin;Bhattacharya, Mallar
重度、难治性哮喘患者存在急性加重死亡风险。细胞因子IL 17 A与严重哮喘的气道炎症相关，迫切需要在该途径中的新的治疗靶点。我们最近发现IL 17 A通过激活促收缩的GT3 RhoA增加气道收缩性。在这里，我们探索靶向的RhoA途径激活IL 17 A抑制RhoA鸟嘌呤核苷酸交换因子（RhoGEFs），RhoA的细胞内激活剂的治疗潜力。我们首先使用核糖体下拉方法通过qPCR分析小鼠气道平滑肌，并在一组RhoGEF中鉴定出高表达的Arhgef 12。通过RNA测序发现，ARHGEF 12也是哮喘患者中最高表达的RhoGEF。来自Arhgef 12-KO小鼠的气管环和用RhoGEF抑制剂处理的WT环具有响应于IL 17 A处理的收缩性降低和RhoA活化的证据。在屋尘螨过敏致敏模型中，Arhgef 12-KO小鼠的气道高反应性降低，但对气道炎症无影响。综上所述，我们的研究结果表明，Arhgef 12是IL 17 A诱导的气道收缩所必需的，并确定了严重哮喘的治疗靶点。
Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.