Ly6 family members in neutrophil biology

项目摘要 中性粒细胞保护免受感染，但也介导炎症组织损伤。结果, 以中性粒细胞为靶点进行治疗将需要详细了解其基本生物学， 集中在中性粒细胞的防御和致病功能可能存在分歧的区域。 在本奖项的第一个周期中，我们探索了两个相关的GPI连接的中性粒细胞表面 功能不佳的蛋白质，小鼠的Ly6G和人类的CD177。我们向大家展示了 这两种蛋白在顺式分子水平上与中性粒细胞表面β2整合素结合，其 因此，结扎可以减少中性粒细胞的迁移。利用……的实验潜力 小鼠炎症模型，我们发现Ly6G结扎选择性地减少了整合素介导的 中性粒细胞滞育的典型迁移向无菌触发，保持整合素不依赖 迁移到感染性刺激时基本不受干扰。我们的初步数据现在显示有证据表明 Ly6G区分小鼠中性粒细胞的亚型，而在人类中，CD177pos和 CD177neg中性粒细胞在基因表达和潜在细胞因子产生方面存在差异。同舟共济 随着第一轮颁奖的成效，这些发现支持了对 这些Ly6家族分子在中性粒细胞生物学中的作用。 我们提出了两个新的、独立的具体目标。Aim I追求的机制是 Ly6G和CD177改变中性粒细胞β2整合素功能，包括寻找新的内源性 反配体。AIM II开发了我们区分中性粒细胞亚型的初步RNAseq数据 基于来自健康捐赠者以及成人和儿童的Ly6G和CD177的表达 患有炎症性关节炎和一过性但严重炎症的川崎病。 综上所述，这些研究将通过定义Ly6家族如何 成员调节2整合素以控制细胞迁移和识别中性粒细胞表型 反映在Ly6G和CD177的差异表达上。

Project Summary Neutrophils protect against infection but also mediate inflammatory tissue injury. As a result, targeting neutrophils therapeutically will require a detailed understanding of their basic biology, focused on domains wherein the defensive and pathogenic functions of neutrophils may diverge. In the first cycle of the present award, we explored two related GPI-linked neutrophil surface proteins of poorly-characterized function, Ly6G in mice and CD177 in humans. We showed that both proteins associate at a molecular level in cis with neutrophil surface β2 integrins and that their ligation thereby attenuates neutrophil migration. Taking advantage of the experimental potential of murine inflammatory models, we found that Ly6G ligation selectively reduced integrin-mediated migration typical for neutrophil diapedesis toward sterile triggers, leaving integrin-independent migration to infectious stimuli largely unperturbed. Our preliminary data now show evidence that Ly6G differentiates subphenotypes within murine neutrophils, while in humans CD177pos and CD177neg neutrophils differ in gene expression and potentially in cytokine production. Together with the productivity of the first cycle of the award, these findings support deeper investigation of the role of these Ly6-family molecules in neutrophil biology. We propose two new and independent specific aims. Aim I pursues the mechanisms by which Ly6G and CD177 alter neutrophil β2 integrin function, including a search for novel endogenous counterligands. Aim II develops our preliminary RNAseq data distinguishing neutrophil subtypes based on expression of Ly6G and CD177, both from healthy donors and from adults and children with inflammatory arthritis and the transient but intensely inflammatory vasculitis Kawasaki disease. Together, these studies will advance the understanding of neutrophils by defining how Ly6 family members regulate 2 integrins to control cell migration and identifying neutrophil phenotypes reflected in differential expression of Ly6G and CD177.