Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation
Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation
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DOI：
10.1016/j.ajpath.2015.10.015
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发表时间：
2016-02-01
影响因子：
6
通讯作者：
Parkos, Charles A.
中科院分区：
文献类型：
--
作者：
Brazil, Jennifer C.;Sumagin, Ronen;Parkos, Charles A.
多形核白细胞（pmn）是先天免疫细胞，其主要功能是从血液迁移到炎症部位，在那里它们发挥重要的抗感染和免疫调节作用。然而，pmn向粘膜上皮组织的迁移失调是慢性炎症性疾病的特征，包括炎症性肠病。糖介导的PMN Lewis聚糖与内皮聚糖结合蛋白之间的结合相互作用对于PMN最初迁移出血管系统至关重要。然而，Lewis聚糖在经上皮迁移（TEM）中的作用尚未得到很好的表征。本研究表明，抗体阻断Lewis X （Le(X)）作为PMN表面末端聚糖残基，阻断趋化性和TEM，同时增强PMN与肠上皮的粘附相互作用。出乎意料的是，靶向糖链中的亚末端Le(x)残基对PMN迁移或粘附相互作用没有影响。TEM后PMN表面Le(x)表达增加，阻断末端Le可调节迁移后PMN功能，增加PMN吞噬和表面调动嗜氮性（CD63、髓过氧化物酶和中性粒细胞弹性酶）和特异性（CD66b和乳铁蛋白）颗粒标记物。这些发现表明，末梢Le(x)是炎症粘膜中调节PMN运输和功能的潜在靶点。此外，考虑到其在迁移的PMN上的丰富表达，Le(x)可能是在PMN内流失调与宿主组织损伤相关的疾病中调节炎症的合理靶点。
Polymorphonuclear leukocytes (PMNs) are innate immune cells whose principal function is to migrate from the blood to sites of inflammation, where they exert crucial anti-infectious and immunomodulatory effects. However, dysregulated migration of PMNs into mucosal epithelial tissues is characteristic of chronic inflammatory disorders, including inflammatory bowel disease. Carbohydrate-mediated binding interactions between PMN Lewis glycans and endothelial glycan-binding proteins are critical for initial migration of PMN out of the vasculature. However, the role of Lewis glycans during transepithelial migration (TEM) has not been well characterized. Herein, we show that antibody blockade of Lewis X (Le(x)) displayed as terminal glycan residues on the PMN surface blocks chemotaxis and TEM while enhancing PMN-adhesive interactions with intestinal epithelia. Unexpectedly, targeting of subterminal Le(x) residues within glycan chains had no effect on PMN migration or adhesive interactions. There was increased surface expression of Le(x) on PMN after TEM, and blockade of terminal Le regulated post-migratory PMN functions, increasing PMN phagocytosis and the surface mobilization of azurophilic (CD63, myeloperoxidase, and neutrophil elastase) and specific (CD66b and lactoferrin) granule markers. These findings suggest that terminal Le(x) represents a potential target for regulating PMN trafficking and function in inflamed mucosa. Furthermore, given its abundant expression on migrating PMN, Le(x) may be a rational target for modulating inflammation in diseases where dysregulated PMN influx is associated with host tissue damage.