Heparanase-Dependent Remodeling of Initial Lymphatic Glycocalyx Regulates Tissue-Fluid Drainage During Acute Inflammation in vivo
Heparanase-Dependent Remodeling of Initial Lymphatic Glycocalyx Regulates Tissue-Fluid Drainage During Acute Inflammation in vivo
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DOI：
10.3389/fimmu.2019.02316
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发表时间：
2019-10-04
影响因子：
7.3
通讯作者：
Voisin, Mathieu-Benoit
中科院分区：
文献类型：
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作者：
Arokiasamy, Samantha;King, Ross;Voisin, Mathieu-Benoit
糖萼是一层致密的碳水化合物链，参与许多基本的生物过程，如细胞和组织的稳态、炎症和疾病的发生。这种结构由膜结合的糖蛋白、硫酸化的蛋白聚糖和糖胺聚糖侧链组成，对血管屏障功能和白细胞迁移特别重要。有趣的是，虽然血管内皮的糖萼已被广泛研究，但对组织相关淋巴管（lv）上的糖萼层的组成和功能知之甚少。在这里，我们使用共聚焦显微镜，使用抗硫酸肝素（HS）抗体和一组识别糖萼不同聚糖部分的凝集素，来表征小鼠肌肌在稳态和炎症条件下初始淋巴毛细血管内皮糖萼的组成。我们的数据显示存在HS， α - d -半乳糖基部分，α 2,3-链唾液酸，在较小程度上，n -乙酰氨基葡萄糖部分。小鼠和人皮肤的lv也有类似的表达谱。有趣的是，tnf刺激引起的小鼠乳突组织或耳部皮肤炎症导致左室糖萼快速（在16小时内）重塑，HS和半乳糖基部分的表达减少，而α 2,3-链唾液酸的水平保持不变。此外，虽然这种反应与血液循环中的中性粒细胞募集及其向组织相关LV的迁移有关，但特异性中性粒细胞耗竭并不影响左室糖萼重塑。从机制上讲，使用非抗凝肝素酶抑制剂抑制LV HS降解而不影响中性粒细胞向LV的迁移。然而，有趣的是，抑制糖萼降解降低了初始lv在急性炎症期间排出间质液的能力。总的来说，我们的数据表明，组织相关lv的内皮糖萼的快速重塑支持液体和大分子的排泄，但在调节中性粒细胞通过初始lv从炎症组织中运输中没有作用。
The glycocalyx is a dense layer of carbohydrate chains involved in numerous and fundamental biological processes, such as cellular and tissue homeostasis, inflammation and disease development. Composed of membrane-bound glycoproteins, sulfated proteoglycans and glycosaminoglycan side-chains, this structure is particularly essential for blood vascular barrier functions and leukocyte diapedesis. Interestingly, whilst the glycocalyx of blood vascular endothelium has been extensively studied, little is known about the composition and function of this glycan layer present on tissue-associated lymphatic vessels (LVs). Here, we applied confocal microscopy to characterize the composition of endothelial glycocalyx of initial lymphatic capillaries in murine cremaster muscles during homeostatic and inflamed conditions using an anti-heparan sulfate (HS) antibody and a panel of lectins recognizing different glycan moieties of the glycocalyx. Our data show the presence of HS, alpha-D-galactosyl moieties, alpha 2,3-linked sialic acids and, to a lesser extent, N-Acetylglucosamine moieties. A similar expression profile was also observed for LVs of mouse and human skins. Interestingly, inflammation of mouse cremaster tissues or ear skin as induced by TNF-stimulation induced a rapid (within 16 h) remodeling of the LV glycocalyx, as observed by reduced expression of HS and galactosyl moieties, whilst levels of alpha 2,3-linked sialic acids remains unchanged. Furthermore, whilst this response was associated with neutrophil recruitment from the blood circulation and their migration into tissue-associated LVs, specific neutrophil depletion did not impact LV glycocalyx remodeling. Mechanistically, treatment with a non-anticoagulant heparanase inhibitor suppressed LV HS degradation without impacting neutrophil migration into LVs. Interestingly however, inhibition of glycocalyx degradation reduced the capacity of initial LVs to drain interstitial fluid during acute inflammation. Collectively, our data suggest that rapid remodeling of endothelial glycocalyx of tissue-associated LVs supports drainage of fluid and macromolecules but has no role in regulating neutrophil trafficking out of inflamed tissues via initial LVs.