Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation.
Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation.
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蛋白酶激活的受体2激活髓样树突状细胞可调节过敏性气道炎症。
DOI：
10.1186/1465-9921-12-122
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发表时间：
2011-09-21
影响因子：
5.8
通讯作者：
Page K
中科院分区：
文献类型：
--
作者：
Lewkowich IP;Day SB;Ledford JR;Zhou P;Dienger K;Wills-Karp M;Page K
过敏原的一个共同特征是它们含有可以激活蛋白酶活化受体（PAR-2）的蛋白酶；然而PAR-2调节过敏性气道炎症的机制尚不清楚。小鼠（野生型和par -2缺陷型）使用德国蟑螂（GC）粪便（草）、从GC草中分离的蛋白酶或通过过继转移GC草处理过的骨髓源树突状细胞（BMDC）致敏，并测量气道炎症（细胞浸润、细胞因子表达和粘蛋白产生）、血清IgE水平和气道高反应性（AHR）。培养BMDC，用GC处理，并评估细胞因子的产生。流式细胞术检测肺mDCs中PAR-2的表达。野生型小鼠暴露于GC草诱导AHR和气道炎症然而par -2缺陷小鼠的反应明显减弱。为了直接研究蛋白酶的作用，我们从GC草中分离出蛋白酶，并在OVA存在的情况下将不含内毒素的蛋白酶注入小鼠气道。GC草蛋白酶足以促进AHR的发展，血清IgE和Th2细胞因子的产生。GC碎屑暴露后，mDC上PAR-2的表达上调，但功能性PAR-2的存在并未改变抗原摄取。为了确定PAR-2激活是否会导致细胞因子的产生差异，我们在GM-CSF存在的情况下培养BMDC，并用GC草处理这些细胞。与野生型小鼠的BMDC相比，缺乏PAR-2的BMDC释放的IL-6、IL-23和TNFα显著减少，表明PAR-2激活在Th2/Th17倾斜的细胞因子产生中很重要。为了确定PAR-2对mDCs在变应性气道炎症发生中的作用，我们将野生型和PAR-2缺陷小鼠的BMDCs分别在存在或不存在GC草的情况下处理，然后过继性地转移到野生型小鼠的气道中。重要的是，GC刺激的野生型BMDC足以诱导AHR和过敏性气道炎症，而GC刺激的par -2缺陷BMDC的反应减弱。综上所述，这些数据表明过敏原PAR-2在mDCs上的激活在介导Th2/Th17细胞因子产生和过敏性气道反应中的重要作用。
A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass-stimulated wild type BMDCs were sufficient to induce AHR and allergic airway inflammation, while GC frass-stimulated PAR-2-deficient BMDC had attenuated responses. Together these data suggest an important role for allergen activation of PAR-2 on mDCs in mediating Th2/Th17 cytokine production and allergic airway responses.
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DOI：
10.1159/000235107
发表时间：
1990-02-01
期刊：
INTERNATIONAL ARCHIVES OF ALLERGY AND APPLIED IMMUNOLOGY
影响因子：
--
作者：
HOLT, PG;SCHONHEGRAD, MA;MCMENAMIN, PG
通讯作者：
MCMENAMIN, PG
影响因子：
4.4
作者：
Schmidlin, F;Amadesi, S;Stevens, ME
通讯作者：
Stevens, ME
影响因子：
4.4
作者：
Ebeling, Cory;Lam, Tong;Vliagoftis, Harissios
通讯作者：
Vliagoftis, Harissios
影响因子：
15.9
作者：
Lambrecht, BN;De Veerman, M;Pauwels, RA
通讯作者：
Pauwels, RA
DOI：
10.1084/jem.20040035
发表时间：
2004-07-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
de Heer HJ;Hammad H;Soullié T;Hijdra D;Vos N;Willart MA;Hoogsteden HC;Lambrecht BN
通讯作者：
Lambrecht BN