Role of Semaphorin 4A in Allergic Inflammation

信号素家族的膜蛋白最初被描述为轴突引导分子。 用于神经元发育的CAL。现在人们认识到，它们在许多生理过程中发挥着关键作用。 以及通过与不同的阵列结合而产生的病理反应，包括血管生成、癌症和炎症 反感受器。最近的研究表明，信号素可以作为共刺激分子。Se- MA4A先前被证明是一种重要的共刺激分子，在体外T细胞激活和在 Th1-体内炎症。Sema4a被证明控制Th1/Th2平衡。然而，我们最近 证明Sema4a在体内过敏性(II型)炎症过程中起到下调作用。 我们观察到过敏性呼吸道炎症增加伴随IL-13升高和Treg降低 过敏原治疗的Sema4a-/-小鼠与WT小鼠的数量比较。有趣的是，过敏性炎症 在WT或Sema4a-/-小鼠中，给予重组可溶性Se-1显著降低 Ma4A。基于这些结果，我们认为Sema4a是Th2驱动的反应的负调控因子。 然而，Sema4a抑制过敏性炎症的机制尚不清楚，这代表了一种 在知识上有很大的差距。因此，这项研究提案的总体目标是确定机制-- NISM通过Sema4a限制过敏性炎症。根据我们的初步数据，我们假设 Sema4a通过与Plexin-B1相互作用来增加细胞数量和活性，从而抑制变态反应性炎症。 特雷格斯的泰。这一假设将通过完成以下具体目标来检验：1)表征 Sema4a/Plexin B1相互作用在控制变态反应性肺炎性T细胞反应中的作用 2)评价丛状蛋白B1在体内对Sema4a抑制活性的贡献，以及3)对 描绘负责Sema4a与丛状蛋白B1相互作用的关键氨基酸。 我们的研究具有确定治疗过敏性炎症的新治疗策略的巨大潜力。

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.