An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma
An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma
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DOI：
10.1007/s10875-012-9798-5
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发表时间：
2013-01-01
影响因子：
9.1
通讯作者：
Kikutani, Hitoshi
中科院分区：
文献类型：
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作者：
Morihana, Tetsuo;Goya, Sho;Kikutani, Hitoshi
目的 IV 类信号蛋白 Sema4A 对于 T(H)1 的有效分化至关重要，而 Sema4a(-/-) 小鼠表现出受损的 TH1 免疫反应。然而，Sema4A 在 T(H)2 细胞介导的过敏性疾病中的作用尚未得到充分研究。本研究的目的是阐明Sema4A在过敏性疾病，特别是过敏性哮喘小鼠模型中的调节作用。方法对BALB/c背景的Sema4a(-/-)小鼠进行过敏性疾病的发展检查。为了诱导实验性哮喘，用卵清蛋白（OVA）致敏小鼠，然后用 OVA 进行鼻内攻击。攻击后，评估气道高反应性（AHR）和气道炎症。使用 Sema4a(-/-) 小鼠和 Sema4A-Fc 融合蛋白检查了 Sema4A 在哮喘中的作用。还检查了 Sema4A-Fc 对抗原特异性效应 CD4(+) T 细胞的直接影响。结果 一小部分 Sema4a(-/-) BALB/c 小鼠自发出现类似于人类特应性皮炎 (AD) 的皮肤损伤。此外，当用 OVA 免疫和攻击时，与野生型 (WT) 小鼠相比，Sema4a(-/-) 小鼠的 AHR、气道炎症和 TH2 型免疫反应得到增强。在攻击期间体内全身施用 Sema4A-Fc 可改善 WT 小鼠的 AHR 和肺部炎症，并减少 TH2 型细胞因子的产生。在缺乏 Tim-2（一种 Sema4A 受体）的小鼠中也观察到了 Sema4A 对气道炎症的抑制作用。最后，我们发现Sema4A-Fc直接抑制产生IL-4的OVA特异性CD4(+) T细胞。结论这些结果表明Sema4A在T(H)2型过敏性疾病，例如过敏性哮喘中发挥抑制作用。
Purpose The class IV semaphorin Sema4A is critical for efficient T(H)1 differentiation and Sema4a(-/-) mice exhibit impaired TH1 immune responses. However, the role of Sema4A in T(H)2 cell-mediated allergic diseases has not been fully studied. The aim of this study was to clarify the regulatory role possessed by Sema4A in mouse models of allergic diseases, particularly allergic asthma.Methods Sema4a(-/-) mice on a BALB/c background were examined for the development of allergic diseases. To induce experimental asthma, mice were sensitized with ovalbumin (OVA) followed by intranasal challenges with OVA. After challenge, airway hyperreactivity (AHR) and airway inflammation were evaluated. The role of Sema4A in asthma was examined using Sema4a(-/-) mice and Sema4A-Fc fusion proteins. The direct effects of Sema4A-Fc on antigen-specific effector CD4(+) T cells were also examined.Results A fraction of Sema4a(-/-) BALB/c mice spontaneously developed skin lesions that resembled atopic dermatitis (AD) in humans. Furthermore, AHR, airway inflammation, and TH2-type immune responses were enhanced in Sema4a(-/-) mice compared to wild type (WT) mice when immunized and challenged with OVA. In vivo systemic administration of Sema4A-Fc during the challenge period ameliorated AHR and lung inflammation and reduced the production of TH2-type cytokines inWT mice. The inhibitory effects of Sema4A on airway inflammation were also observed in mice deficient in Tim-2, a Sema4A receptor. Finally, we showed that Sema4A-Fc directly inhibited IL-4-producing OVA-specific CD4(+) T cells.Conclusion These results demonstrate that Sema4A plays an inhibitory role in T(H)2-type allergic diseases, such as allergic asthma.