Pharmacology & Experimental Therapeutics, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Clin Exp Allergy. 2014 Nov;44(11):1335-46. doi: 10.1111/cea.12422.
Allergy is characterized by eosinophilia and an increased susceptibility to microbial infection. Atopic dermatitis (AD) is typically associated with Staphylococcus aureus (SA) colonization. Some of the mechanisms by which SA and its exotoxins interact with eosinophils remain elusive. CD48, a glycosylphosphatidylinositol-anchored receptor belonging to the CD2 family, participates in mast cells-SA stimulating cross-talk, facilitates the formation of the mast cell/eosinophils effector unit and as expressed by eosinophils, mediates experimental asthma.
To investigate the role of CD48 expressed on human peripheral blood and mouse bone marrow-derived eosinophils (BMEos) in their interaction with heat-killed SA and its three exotoxins, Staphylococcal enterotoxin B (SEB), protein A (PtA) and peptidoglycan (PGN).
Eosinophils were obtained from human peripheral blood and BM of WT and CD48-/- mice. SA was heat killed and eosinophils-SA/exotoxins interactions were analyzed by confocal microscopy, adhesion and degranulation, cell viability, cytokine release and cell signalling. In addition, peritonitis was induced by SEB injection into CD48-/- and WT mice. CD48 expression was studied in AD patients' skin and as expressed on their leucocytes in the peripheral blood.
We provide evidence for the recognition and direct physical interaction between eosinophils and SA/exotoxins. Skin of AD patients showed a striking increase of eosinophil-associated CD48 expression while on peripheral blood leucocytes it was down-regulated. SA/exotoxins enhanced CD48 eosinophil expression, bound to CD48 and caused eosinophil activation and signal transduction. These effects were significantly decreased by blocking CD48 on human eosinophils or in BMEos from CD48-/- mice. We have also explored the role of CD48 in a SEB-induced peritonitis model in CD48-/- mice by evaluating inflammatory peritoneal cells, eosinophil numbers and activation.
These data demonstrate the important role of CD48 in SA/exotoxins-eosinophil activating interactions that can take place during allergic responses and indicate CD48 as a novel therapeutic target for allergy and especially of AD.
过敏的特征是嗜酸性粒细胞增多和对微生物感染的易感性增加。特应性皮炎（AD）通常与金黄色葡萄球菌（SA）定植有关。SA 及其外毒素与嗜酸性粒细胞相互作用的一些机制仍不清楚。CD48 是一种糖基磷脂酰肌醇锚定受体，属于 CD2 家族，参与肥大细胞-SA 刺激的串扰，促进肥大细胞/嗜酸性粒细胞效应单位的形成，并且在嗜酸性粒细胞上表达，介导实验性哮喘。
研究人外周血和鼠骨髓来源嗜酸性粒细胞（BMEos）上表达的 CD48 在其与热灭活 SA 及其三种外毒素金黄色葡萄球菌肠毒素 B（SEB）、蛋白 A（PtA）和肽聚糖（PGN）相互作用中的作用。
从 WT 和 CD48-/- 小鼠的外周血和 BM 中获得嗜酸性粒细胞。SA 被热灭活，通过共聚焦显微镜、粘附和脱颗粒、细胞活力、细胞因子释放和细胞信号转导分析嗜酸性粒细胞-SA/外毒素的相互作用。此外，通过向 CD48-/- 和 WT 小鼠注射 SEB 诱导腹膜炎。研究了 AD 患者皮肤中的 CD48 表达以及外周血白细胞中的表达。
我们提供了嗜酸性粒细胞与 SA/外毒素直接识别和直接物理相互作用的证据。AD 患者的皮肤显示出嗜酸性粒细胞相关 CD48 表达的显著增加，而在外周血白细胞中则下调。SA/外毒素增强了 CD48 嗜酸性粒细胞的表达，与 CD48 结合，并导致嗜酸性粒细胞的激活和信号转导。这些作用在人嗜酸性粒细胞或 CD48-/- 小鼠的 BMEos 中阻断 CD48 后显著降低。我们还通过评估炎症性腹膜细胞、嗜酸性粒细胞数量和激活，在 CD48-/- 小鼠的 SEB 诱导性腹膜炎模型中探索了 CD48 的作用。
这些数据表明 CD48 在 SA/外毒素-嗜酸性粒细胞激活相互作用中起着重要作用，这种相互作用可能发生在过敏反应中，并表明 CD48 是过敏特别是 AD 的一种新的治疗靶点。
