N-Glycans Differentially Regulate Eosinophil and Neutrophil Recruitment during Allergic Airway Inflammation
N-Glycans Differentially Regulate Eosinophil and Neutrophil Recruitment during Allergic Airway Inflammation
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DOI：
10.1074/jbc.m111.279554
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发表时间：
2011-11-04
影响因子：
4.8
通讯作者：
Sriramarao, P.
中科院分区：
文献类型：
--
作者：
Bahaie, Nooshin S.;Kang, Bit Na;Sriramarao, P.
过敏性气道炎症，包括哮喘，通常以嗜酸性粒细胞的主要募集为特征。然而，在严重加重期间，嗜中性粒细胞也很突出。细胞表面表达的聚糖在炎症期间的白细胞运输和募集中起作用。在此，研究了UDP-N-乙酰葡糖胺：α-6-D-甘露糖苷β 1，6-N-乙酰葡糖胺转移酶V（MGAT 5）修饰的N-聚糖在过敏性气道炎症期间嗜酸性粒细胞和中性粒细胞募集中的参与。与WT小鼠相比，过敏原激发的Mgat5缺陷（Mgat5（-/-））小鼠表现出显著减弱的气道嗜酸性粒细胞增多和炎症（Th2细胞因子减少，粘液产生），这归因于Mgat5（-/-）嗜酸性粒细胞的滚动、粘附和存活减少。有趣的是，过敏原激发的Mgat5（-/-）小鼠发展出气道嗜中性粒细胞，并且气道反应性增加，促炎细胞因子（IL-17 A、TNF α、IFN γ）水平持续升高。在Mgat5（-/-）小鼠中的LPS和巯基乙酸盐（TG）诱导的炎症中也观察到这种增加的中性粒细胞募集。此外，在TG暴露的WT小鼠的腹膜腔中，与WT中性粒细胞相比，输注的Mgat5（-/-）中性粒细胞的募集显著增加。与WT中性粒细胞相比，Mgat5（-/-）中性粒细胞在体外表现出对P-选择素的粘附增强以及向角质形成细胞衍生的趋化因子的迁移增加，以及在激活和表达升高水平的CXCR2时钙动员增加，这可能有助于增加中性粒细胞募集。这些数据表明MGAT5修饰的N-聚糖在过敏性气道炎症期间嗜酸性粒细胞和中性粒细胞募集的差异调节中具有重要作用。
Allergic airway inflammation, including asthma, is usually characterized by the predominant recruitment of eosinophils. However, neutrophilia is also prominent during severe exacerbations. Cell surface-expressed glycans play a role in leukocyte trafficking and recruitment during inflammation. Here, the involvement of UDP-N-acetylglucosamine:alpha-6-D-mannoside beta 1,6-N-acetylglucosaminyltransferase V (MGAT5)-modified N-glycans in eosinophil and neutrophil recruitment during allergic airway inflammation was investigated. Allergen-challenged Mgat5-deficient (Mgat5(-/-)) mice exhibited significantly attenuated airway eosinophilia and inflammation (decreased Th2 cytokines, mucus production) compared with WT counterparts, attributable to decreased rolling, adhesion, and survival of Mgat5(-/-) eosinophils. Interestingly, allergen-challenged Mgat5(-/-) mice developed airway neutrophilia and increased airway reactivity with persistent elevated levels of proinflammatory cytokines (IL-17A, TNF alpha, IFN gamma)). This increased neutrophil recruitment was also observed in LPS- and thioglycollate (TG)-induced inflammation in Mgat5(-/-) mice. Furthermore, there was significantly increased recruitment of infused Mgat5(-/-) neutrophils compared with WT neutrophils in the peritoneal cavity of TG-exposed WT mice. Mgat5(-/-) neutrophils demonstrated enhanced adhesion to P-selectin as well as increased migration toward keratinocyte-derived chemokine compared with WT neutrophils in vitro along with increased calcium mobilization upon activation and expression of elevated levels of CXCR2, which may contribute to the increased neutrophil recruitment. These data indicate an important role for MGAT5-modified N-glycans in differential regulation of eosinophil and neutrophil recruitment during allergic airway inflammation.