Role of Semaphorin 4A in Allergic Inflammation

semaphorin家族的膜蛋白最初的特点是轴突导向分子的关键， 神经元发育的标志。现在人们认识到，它们在许多生理学过程中起着关键作用。 和病理反应，包括血管生成、癌症和炎症， 反受体。最近的研究表明，脑信号蛋白可以作为共刺激分子。塞- ma 4A以前被证明是体外T细胞活化和体外T细胞增殖的重要共刺激分子。 Th 1-体内炎症。Sema 4A被证明控制Th 1/Th 2平衡。然而，我们最近 证明Sema 4A在体内过敏性（II型）炎症过程中发挥下调作用。 我们观察到过敏性气道炎症的增加伴随着IL-13的增加和Treg的降低 与WT小鼠相比，过敏原处理的Sema 4A-/-小鼠中的数量。有趣的是，过敏性炎症 在WT或Sema 4A-/-小鼠中，通过给予重组可溶性Se- ma4A。基于这些结果，我们提出Sema 4A是Th 2驱动反应的负调节因子。 然而，Sema 4A抑制过敏性炎症的机制尚不清楚，这代表了一种可能的机制。 知识的巨大差距。因此，本研究提案的总体目标是确定机制- Sema 4A通过其限制过敏性炎症。根据我们的初步数据，我们假设， Sema 4A通过与丛状蛋白-B1相互作用来限制过敏性炎症，以增加其数量和活性。 泰的。这一假设将通过完成以下具体目标来检验：1）表征 Sema 4A/丛蛋白B1相互作用在变应性肺炎中T细胞应答控制中的作用 2）评估丛蛋白B1对Sema 4A体内抑制活性的贡献，和3） 描述了负责Sema 4A与丛蛋白B1相互作用的关键氨基酸。 我们的研究具有重要的潜力，以确定新的治疗策略来治疗过敏性炎症。

The semaphorin family of membrane proteins was initially characterized as axon-guidance molecules criti- cal for neuronal development. It is now recognized that they play critical roles in a number of physiological and pathologic responses including angiogenesis, cancer, and inflammation by binding to a diverse array of counter receptors. Recent studies suggest that semaphorins can act as co-stimulatory molecules. Se- ma4A was previously shown to be an important co-stimulatory molecule for T-cell activation in vitro and for Th1-inflammation in vivo. Sema4A was shown to control the Th1/Th2 balance. However, we recently demonstrated that Sema4A played a down-regulatory role during allergic (Type II) inflammation in vivo. We observed increased allergic airway inflammation accompanied by increased IL-13 and lower Treg numbers in allergen-treated Sema4A-/- mice compared to WT mice. Interestingly, allergic inflammation was significantly reduced in either WT or Sema4A-/- mice by administration of recombinant soluble Se- ma4A. Based on these results, we propose that Sema4A is a negative regulator of Th2-driven responses. However, the mechanism by which Sema4A dampens allergic inflammation is unknown, representing a significant gap in knowledge. Thus, the overall goal of this research proposal is to determine the mecha- nism by which Sema4A limits allergic inflammation. Based on our preliminary data, we hypothesize that Sema4A limits allergic inflammation through interaction with Plexin-B1 to enhance the numbers and activi- ty of Tregs. This hypothesis will be tested by completing the following specific aims: 1) to characterize the contribution of Sema4A / Plexin B1 interaction in the control of T cell responses in allergic lung inflamma- tion, 2) to evaluate the contribution of Plexin B1 to the suppressive activity of Sema4A in vivo, and 3) to delineate the critical amino acids responsible for Sema4A interaction with Plexin B1. Our research has significant potential to identify novel therapeutic strategies to treat allergic inflammation.