Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, Ohio.
Key Laboratory of National Health Commission on Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasitic and Vector Control, Jiangsu Institute of Parasitic Diseases and Public Health Research Center, Jiangnan University, Wuxi, Jiangsu, China.
Clin Exp Allergy. 2019 Jan;49(1):92-107. doi: 10.1111/cea.13293. Epub 2018 Nov 13.
Asthma is an allergic airway inflammation-driven disease that affects more than 300 million people world-wide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development cannot be prevented. Cdc42 GTPase has been shown to regulate actin cytoskeleton, cell proliferation and survival.
To investigate the role and targeting of Cdc42 in Th2 cell differentiation and Th2-mediated allergic airway inflammation.
Post-thymic Cdc42-deficient mice were generated by crossing Cdc42 mice with dLck transgenic mice in which Cre expression is driven by distal Lck promoter. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on Th2 cell differentiation were evaluated in vitro under Th2-polarized culture conditions. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on allergic airway inflammation were evaluated in ovalbumin- and/or house dust mite-induced mouse models of asthma.
Post-thymic deletion of Cdc42 led to reduced peripheral CD8 T cells and attenuated Th2 cell differentiation, with no effect on closely related Th1, Th17 and induced regulatory T (iTreg) cells. Post-thymic Cdc42 deficiency ameliorated allergic airway inflammation. The selective inhibition of Th2 cell differentiation by post-thymic deletion of Cdc42 was recapitulated by pharmacological targeting of Cdc42 with CASIN, a Cdc42 activity-specific chemical inhibitor. CASIN also alleviated allergic airway inflammation. CASIN-treated Cdc42-deficient mice showed comparable allergic airway inflammation to vehicle-treated Cdc42-deficient mice, indicative of negligible off-target effect of CASIN. CASIN had no effect on established allergic airway inflammation.
Cdc42 is required for Th2 cell differentiation and allergic airway inflammation, and rational targeting Cdc42 may serve as a preventive but not therapeutic approach for asthma control.
哮喘是一种过敏性气道炎症驱动的疾病，影响着全球超过 3 亿人。哮喘的靶向治疗方法还很缺乏。虽然可以预防哮喘症状恶化，但无法预防哮喘的发展。CDC42 GTPase 已被证明可以调节肌动蛋白细胞骨架、细胞增殖和存活。
研究 CDC42 在 Th2 细胞分化和 Th2 介导的过敏性气道炎症中的作用和靶向性。
通过将 Cdc42 小鼠与 dLck 转基因小鼠杂交，在 dLck 启动子的远端驱动 Cre 表达，生成胸腺后 Cdc42 缺陷小鼠。在 Th2 极化培养条件下，评估胸腺后 Cdc42 缺失和药理学靶向 Cdc42 对 Th2 细胞分化的影响。在卵清蛋白和/或屋尘螨诱导的哮喘小鼠模型中，评估胸腺后 Cdc42 缺失和药理学靶向 Cdc42 对过敏性气道炎症的影响。
胸腺后 Cdc42 的缺失导致外周 CD8 T 细胞减少，并减弱 Th2 细胞分化，但对密切相关的 Th1、Th17 和诱导性调节性 T 细胞（iTreg）没有影响。胸腺后 Cdc42 缺陷减轻了过敏性气道炎症。通过使用 CASIN（一种 CDC42 活性特异性化学抑制剂）对 Th2 细胞分化进行胸腺后 Cdc42 缺失的选择性抑制，再现了对过敏性气道炎症的抑制作用。CASIN 也减轻了过敏性气道炎症。与 vehicle 处理的 Cdc42 缺陷小鼠相比，用 CASIN 处理的 Cdc42 缺陷小鼠的过敏性气道炎症相似，表明 CASIN 的脱靶效应可以忽略不计。CASIN 对已建立的过敏性气道炎症没有影响。
CDC42 是 Th2 细胞分化和过敏性气道炎症所必需的，合理靶向 Cdc42 可能是一种预防而非治疗哮喘的方法。
