Siglec-F and Resolution of Allergic Inflammation

摘要 虽然关于过敏性疾病中炎性反应的诱导已知很多 炎症，对自然下降的内源性机制了解更少- 调节过敏性炎症反应。这些内源性反应可能 有可能被利用来开发新的抗炎疗法 过敏症。在这项提案中，我们建议调查 唾液酸结合免疫球蛋白超家族凝集素-F细胞表面受体的激活 在下调变态反应性炎症反应和组织重塑反应中的作用 发炎。Siglec-F在与过敏性炎症相关的细胞上高表达 比如嗜酸性粒细胞。Siglec-F受体在调节变态反应中的作用 从ITIM基序知道的细胞质尾部的存在推测了反应 参与免疫系统中的抑制性信号通路。因此，我们 建议确定1)Siglec-F发挥这种抗过敏作用的机制 体内和体外，以及2)鉴定和表征Siglec-F的特异性配体 在体内的过敏性炎症反应中由上皮细胞产生，(因为它们 名称意味着Siglecs与表达多糖唾液酸的配体结合)，以及3) 鉴定Siglec-8(小鼠Siglec-F的人类同源基因)和Siglec-8的表达 其配体位于哮喘患者的嗜酸性炎症部位。

Abstract While much is known about the induction of the inflammatory response in allergic inflammation, far less is understood about endogenous mechanisms that naturally down- regulate allergic inflammatory responses. These endogenous responses could potentially be harnessed to develop novel anti-inflammatory therapies for hypersensitivity diseases. In this proposal we propose to investigate the role that activation of Siglec-F (Sialic acid-binding Ig-superfamily lectin-F) cell surface receptors play in down-regulating the inflammatory, and tissue remodeling response in allergic inflammation. Siglec-F is highly expressed on cells associated with allergic inflammation such as eosinophils. A functional role for Siglec-F receptors in regulating allergic responses is suggested from the presence in their cytoplasmic tails of ITIM motifs know to be involved in inhibitory signaling pathways in the immune system. We therefore propose to determine 1) the mechanisms by which Siglec-F exerts this anti-allergic effect in vivo and in vitro, and 2) identify and characterize ligands specific for Siglec-F that may be generated by epithelium during an allergic inflammatory response in vivo, (as their name implies Siglecs bind to ligands expressing the glycan sialic acid), and 3) characterize the expression of Siglec-8 (the human orthologue of mouse Siglec-F) and its ligand at sites of eosinophilic inflammation in humans with asthma.