Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes.
Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes.
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DOI：
10.1080/01902148.2018.1451574
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发表时间：
2018-03
影响因子：
1.7
通讯作者：
Sriramarao P
中科院分区：
文献类型：
--
作者：
Ge XN;Bastan I;Ha SG;Greenberg YG;Esko JD;Rao SP;Sriramarao P
HSPG是含有共价连接的硫酸乙酰肝素（HS）链的糖蛋白，其结合生长因子、趋化因子等，并调节炎症的各个方面，包括细胞募集。我们先前表明，内皮N-乙酰葡糖胺N-脱乙酰基酶-N-磺基转移酶-1（Ndst1），一种在HS生物合成过程中负责N-硫酸化的酶，缺失可减少气道过敏性炎症（AAI）。在这里，我们调查的重要性，O-硫酸化介导的糖醛酸2-O-磺基转移酶（Hs2st）在发展AAI相对于N-硫酸化。用链格孢菌攻击内皮细胞和白细胞Hs2st（Hs2stf/fTie2Cre+）或Ndst1（Ndst1f/fTie2Cre+）缺陷的小鼠和WT小鼠，并评价气道炎症。在体外流动条件下，研究了鼠嗜酸性粒细胞在肺内皮细胞上的运输。暴露于链格孢菌降低了WT小鼠中Hs2st的表达水平，而Ndst 1的水平保持不变。与WT小鼠相比，链格孢菌攻击的Hs2stf/fTie2Cre+小鼠在骨髓、支气管肺泡灌洗液[BALF]和肺组织中表现出显著增加的嗜酸性粒细胞，与持续的气道高反应性、气道粘液高分泌和升高的Th2细胞因子相关。相比之下，链格孢菌激发的Ndst1f/fTie2Cre+小鼠与WT小鼠相比，气道嗜酸性粒细胞增多、粘液分泌和平滑肌质量显著降低。虽然在链格孢菌攻击的Hs2stf/fTie2Cre+小鼠中BALF嗜酸细胞活化趋化因子相对于WT小鼠较低，但它们没有像变应原攻击的Ndst1f/fTie2Cre+小鼠中那样降低至背景水平。鼠嗜酸性粒细胞在体外流动条件下的运输在Hs2st缺陷和WT内皮细胞上是相似的。ZO-1在对照组和过敏原激发组小鼠的Hs2st缺陷型肺血管中的表达显著低于WT小鼠。我们的研究表明，过敏原暴露减少表达Hs2st;损失的糖醛酸2-O-硫酸化的内皮细胞和白细胞HSPG放大招聘的嗜酸性粒细胞可能由于受损的血管内皮细胞导致持续性炎症，而损失的N-硫酸化限制嗜酸性粒细胞增多症和减轻炎症强调的重要性，位点特异性硫酸化的HSPG在AAI中的作用。
HSPGs are glycoproteins containing covalently attached heparan sulfate (HS) chains which bind to growth factors, chemokines, etc., and regulate various aspects of inflammation including cell recruitment. We previously showed that deletion of endothelial N-acetylglucosamine N-deacetylase-N-sulfotransferase-1 (Ndst1), an enzyme responsible for N-sulfation during HS biosynthesis, reduces airway allergic inflammation (AAI). Here, we investigated the importance of O-sulfation mediated by uronyl 2-O-sulfotransferase (Hs2st) in development of AAI relative to N-sulfation. Mice deficient in endothelial and leukocyte Hs2st (Hs2stf/fTie2Cre+) or Ndst1 (Ndst1f/fTie2Cre+) and WT mice were challenged with Alternaria alternata and evaluated for airway inflammation. Trafficking of murine eosinophils on lung endothelial cells was examined in vitro under conditions of flow. Exposure to Alternaria decreased expression level of Hs2st in WT mice while level of Ndst1 remained unchanged. Compared to WT mice, Alternaria-challenged Hs2stf/fTie2Cre+ mice exhibited significantly increased eosinophils in the bone marrow, bronchoalveolar lavage fluid [BALF] and lung tissue associated with persistent airway hyperresponsiveness, airway mucus hypersecretion and elevated Th2 cytokines. In contrast, Alternaria-challenged Ndst1f/fTie2Cre+ mice exhibited a marked reduction in airway eosinophilia, mucus secretion and smooth muscle mass compared to WT counterparts. While BALF eotaxins were lower in Alternaria-challenged Hs2stf/fTie2Cre+ relative to WT mice, they were not reduced to background levels as in allergen-challenged Ndst1f/fTie2Cre+ mice. Trafficking of murine eosinophils under conditions of flow in vitro was similar on Hs2st-deficient and WT endothelial cells. Expression of ZO-1 in Hs2st-deficient lung blood vessels in control and allergen-challenged mice was significantly lower than in WT counterparts. Our study demonstrates that allergen exposure reduces expression of Hs2st; loss of uronyl 2-O-sulfation in endothelial and leukocyte HSPG amplifies recruitment of eosinophils likely due to a compromised vascular endothelium resulting in persistent inflammation whereas loss of N-sulfation limits eosinophilia and attenuates inflammation underscoring the importance of site-specific sulfation in HSPG to their role in AAI.
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影响因子：
16.6
作者：
Ha, Sung Gil;Ge, Xiao Na;Bahaie, Nooshin S.;Kang, Bit Na;Rao, Amrita;Rao, Savita P.;Sriramarao, P.
通讯作者：
Sriramarao, P.
DOI：
10.4049/jimmunol.1102253
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bahaie NS;Hosseinkhani MR;Ge XN;Kang BN;Ha SG;Blumenthal MS;Jessberger R;Rao SP;Sriramarao P
通讯作者：
Sriramarao P
影响因子：
3.4
作者：
Capaldo, Christopher T.;Nusrat, Asma
通讯作者：
Nusrat, Asma
影响因子：
5.6
作者：
Hull EE;Montgomery MR;Leyva KJ
通讯作者：
Leyva KJ
影响因子：
20.3
作者：
Axelsson, Jakob;Xu, Ding;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.