ROCK2在小鼠过敏性气道反应CD4 +细胞中的作用
2017/07/24
背景：Rho激酶（ROCKs）可促进过敏性气道疾病的发生。ROCKs在淋巴细胞增殖和迁移中也起作用。
目的：确定ROCK2在CD4 +细胞中对过敏性气道反应的作用。
方法：ROCK2-单倍体不足（ROCK2 +/-）和野生型小鼠用卵清蛋白（OVA）致敏。然后在用OVA雾化进行激发的48小时前，ROCK2 +/-小鼠接受来自ROCK2-充足的OVA TCR转基因（OT-II）小鼠的CD4 +细胞或盐水。野生型小鼠在激发前接受盐水。在最后一次激发48小时后测定过敏性气道反应。在仅CD4 +细胞缺乏ROCK2的小鼠（ROCK2CD4Cre小鼠）与对照小鼠（CD4-Cre和ROCK2flox / flox）中评估过敏性气道反应。
结果：与野生型小鼠相比，ROCk2 +/-小鼠中OVA诱导的支气管肺泡灌洗淋巴细胞，嗜酸粒细胞、IL-13、IL-5和嗜酸粒细胞活化趋化因子的增加均降低，气道高反应性和粘液高分泌也是如此。在ROCK2 +/-小鼠中，来自OT-II小鼠CD4 +细胞的过继转移恢复了OVA对淋巴细胞、嗜酸粒细胞、IL-13、IL-5和粘液分泌的影响，进而达到野生型小鼠的水平，而嗜酸粒细胞活化趋化因子和气道高反应性不受到影响。ROCK2抑制剂降低了IL-13诱导的嗜酸粒细胞活化趋化因子从气道平滑肌（ASM）的释放，与这些抑制剂对ASM收缩力的影响相类似。尽管过继转移能够恢复ROCK2功能不足小鼠的过敏性气道炎症，但ROCK2CD4Cre与对照小鼠的过敏性炎症并无差异。
结论：ROCK2可能通过淋巴细胞活化和迁移进入气道的ASM细胞和非淋巴细胞内起作用，进而引起过敏性气道反应。
Role of ROCK2 in CD4+ cells in allergic airways responses in mice
D. I. Kasahara,J. A. Mathews,F. M. C. Ninin,A. P. Wurmbrand,J. K. Liao,S. A. Shore
Clinical & Experimental Allergy;2017;47;224-235
Background：Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration.
Objective：To determine the role of ROCK2 acting within CD4+ cells in allergic airways responses.
Methods：ROCK2-haplo insufficient (ROCK2+/−) and wild-type mice were sensitized with ovalbumin (OVA). ROCK2+/− mice then received either CD4+ cells from ROCK2-sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 h before challenge with aerosolized OVA. Wild-type mice received saline before challenge. Allergic airways responses were measured 48 h after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4+ cells (ROCK2CD4Cre mice) vs. control (CD4-Cre and ROCK2flox/flox) mice.
Results：OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2+/− vs. wild-type mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2+/− mice, adoptive transfer with CD4+ cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wild-type levels, whereas eotaxin and airway hyperresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2-insufficient mice, allergic inflammation was not different in ROCK2CD4Cre vs. control mice.
Conclusion：ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non-lymphocyte cells involved in lymphocyte activation and migration into the airways.
目的：确定ROCK2在CD4 +细胞中对过敏性气道反应的作用。
方法：ROCK2-单倍体不足（ROCK2 +/-）和野生型小鼠用卵清蛋白（OVA）致敏。然后在用OVA雾化进行激发的48小时前，ROCK2 +/-小鼠接受来自ROCK2-充足的OVA TCR转基因（OT-II）小鼠的CD4 +细胞或盐水。野生型小鼠在激发前接受盐水。在最后一次激发48小时后测定过敏性气道反应。在仅CD4 +细胞缺乏ROCK2的小鼠（ROCK2CD4Cre小鼠）与对照小鼠（CD4-Cre和ROCK2flox / flox）中评估过敏性气道反应。
结果：与野生型小鼠相比，ROCk2 +/-小鼠中OVA诱导的支气管肺泡灌洗淋巴细胞，嗜酸粒细胞、IL-13、IL-5和嗜酸粒细胞活化趋化因子的增加均降低，气道高反应性和粘液高分泌也是如此。在ROCK2 +/-小鼠中，来自OT-II小鼠CD4 +细胞的过继转移恢复了OVA对淋巴细胞、嗜酸粒细胞、IL-13、IL-5和粘液分泌的影响，进而达到野生型小鼠的水平，而嗜酸粒细胞活化趋化因子和气道高反应性不受到影响。ROCK2抑制剂降低了IL-13诱导的嗜酸粒细胞活化趋化因子从气道平滑肌（ASM）的释放，与这些抑制剂对ASM收缩力的影响相类似。尽管过继转移能够恢复ROCK2功能不足小鼠的过敏性气道炎症，但ROCK2CD4Cre与对照小鼠的过敏性炎症并无差异。
结论：ROCK2可能通过淋巴细胞活化和迁移进入气道的ASM细胞和非淋巴细胞内起作用，进而引起过敏性气道反应。
(黄丹1 张红萍1 王刚1 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Clinical & Experimental Allergy;2017;47;224-235）
（Clinical & Experimental Allergy;2017;47;224-235）
Role of ROCK2 in CD4+ cells in allergic airways responses in mice
D. I. Kasahara,J. A. Mathews,F. M. C. Ninin,A. P. Wurmbrand,J. K. Liao,S. A. Shore
Clinical & Experimental Allergy;2017;47;224-235
Background：Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration.
Objective：To determine the role of ROCK2 acting within CD4+ cells in allergic airways responses.
Methods：ROCK2-haplo insufficient (ROCK2+/−) and wild-type mice were sensitized with ovalbumin (OVA). ROCK2+/− mice then received either CD4+ cells from ROCK2-sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 h before challenge with aerosolized OVA. Wild-type mice received saline before challenge. Allergic airways responses were measured 48 h after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4+ cells (ROCK2CD4Cre mice) vs. control (CD4-Cre and ROCK2flox/flox) mice.
Results：OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2+/− vs. wild-type mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2+/− mice, adoptive transfer with CD4+ cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wild-type levels, whereas eotaxin and airway hyperresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2-insufficient mice, allergic inflammation was not different in ROCK2CD4Cre vs. control mice.
Conclusion：ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non-lymphocyte cells involved in lymphocyte activation and migration into the airways.
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