The Role of CD13 and its activators in vascular inflammation

CD13/氨基肽酶N细胞表面肽酶表达于活化的内皮细胞和正常人 髓系细胞包括单核细胞、粒细胞、巨噬细胞、树突状细胞和肥大细胞。我们 发现单核细胞或内皮细胞与激活的CD13单抗发生交联 以一种信号转导依赖的方式显著增强细胞间的黏附，这与 模拟调节细胞黏附的天然CD13激活剂的抗体。达成一致，而他们的 造血谱正常，CD13基因缺失小鼠的巨噬细胞功能明显受损 黏附内皮细胞单层，提示CD13参与炎性单核细胞/内皮细胞 互动。此外，缺乏CD13的小鼠在多发性硬化症模型中完全受到保护， 强烈暗示在炎症性自身免疫机制中也起着关键作用。对该事件的调查 相关的分子机制表明，可溶性重组CD13阻断了这种黏附，激活了 单核细胞与固定化重组CD13黏附，单核细胞与内皮细胞CD13黏附 在单一的免疫复合体中发现，表明CD13直接参与了黏附。此外， 粘附性严格依赖于唾液酸基，这意味着唾液酸结合蛋白的作用。 CD13黏附中的DsiglecsD。鉴定CD13激活剂的生理来源--小鼠血清 经历过敏反应或动脉粥样硬化，但没有其他炎症性侮辱会增加 CDI依赖的单核细胞/内皮细胞黏附，因此我们可以从蛋白质组学上鉴定这一有趣的现象 CDIS特异的炎症调节因子，指示新的细胞与细胞之间的相互作用，以响应特定的 挑战。总的来说，这些数据支持CD13作为分子界面的作用，它诱导和 参与关键的炎性细胞相互作用，并可能提供关于高水平的 血清唾液酸与心血管疾病有关。实验计划将解剖亲缘关系 条件性CD13缺失动物体内单核细胞CD13在炎症过程中的作用 炎症模型。此外，我们还将确定CD13通过哪些新的分子机制 相关性(请参阅说明)： 炎症与许多人类疾病的进展有关，如心血管疾病、糖尿病、 类风湿性关节炎和癌症。在这些疾病中，保护机制通常会变得不平衡 并导致组织损伤和疾病加重。了解分子和机理 调节正常的功能对于控制疾病中的正常功能失调至关重要。

The CD13/aminopeptidase N cell surface peptidase is expressed on activated endothelial cells and normal cells of the myeloid lineage including monocytes, granulocytes, macrophages dendritic, and mast cells. We find that crosslinking of either monocytes or endothelial cells with activating monoclonal antibodies to CD13 significantly enhances cell-cell adhesion in a signal transduction dependent manner consistent with the antibody mimicking a natural CD13 activator that regulates cell adhesion. In agreement, while their hematopoietic profiles are normal, macrophages from CD13 null mice are significantly impaired in their ability to adhere to endothelial monolayers, suggesting CD13 participates in inflammatory monocyte/endothelial interactions. In addition, mice lacking CD13 are completely protected in a model of multiple sclerosis, strongly implicating a critical role in inflammatory autoimmune mechanisms as well. Investigation into the relevant molecular mechanisms showed that soluble recombinant CD13 blocks this adhesion, activated monocytes adhere to immobilized recombinant CD13 and both monocyte and endothelial cell CD13 are found in a single immunocomplex, suggesting that CD13 directly participates in the adhesion. Furthermore, adhesion is strictly dependent on sialyl moieties, implicating a role for the sialic acid binding proteins DSiglecsD in CD13 adhesion. To identify a physiologic source of the CD13 activator, serum from mice undergoing hypersensitivity reactions or atherosclerosis but not other inflammatory insults increases CDIS-dependent monocyte/endothelial adhesion, thus we can proteomically identify this intriguing CDIS-specific inflammatory regulator that dictates novel cell-cell interactions in response to specific challenges. Collectively, these data support a role for CD13 as a molecular interface that induces and participates in critical inflammatory cell interactions and may provide insights regarding the high levels of serum sialic acid associated with cardiovascular disease. The experimental plan will dissect the relative contribution of monocytic CD13 to inflammatory processes using conditional CD13 null animals in in vivo models of inflammation. In addition, we will identify the novel molecular mechanisms by which CD13 RELEVANCE (See instructions): Inflammation is linked to the progression of many human diseases such as cardiovascular disease, diabetes, rheumatoid arthritis, and cancer. In these diseases normally protective mechanisms become unbalanced and lead to tissue damage and intensification of disease. Understanding the molecules and mechanisms that regulate normal functions is critical to controlling their dysregulation in disease.