Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation.
Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation.
复制标题
DOI：
10.4049/jimmunol.1201865
复制
发表时间：
2012-11-01
期刊：
影响因子：
--
通讯作者：
Kanaoka Y
中科院分区：
文献类型：
--
作者：
Barrett NA;Fernandez JM;Maekawa A;Xing W;Li L;Parsons MW;Austen KF;Kanaoka Y
半胱氨酰白三烯（cys-LTs）可通过树突状细胞（DCs）上的1型受体CysLT 1 R介导Th 2免疫应答。然而，同源2型受体CysLT 2 R在Th 2免疫中的作用是未知的。Df致敏和CysLT 2 R缺陷小鼠的挑战表明，嗜酸性粒细胞性肺部炎症，血清IgE和Th 2细胞因子的显着增加。通过过继转移Df脉冲的CysLT 2 R缺陷型骨髓来源的DC（BMDC）致敏的野生型（WT）小鼠在再刺激的肺门淋巴结中也具有Df引起的嗜酸性肺炎症和Th 2细胞因子的显著增加。这种反应是不存在的Df脉冲BMDC致敏的小鼠缺乏白三烯C4合酶（LTC 4S），CysLT 1 R，或CysLT 2 R/LTC 4S，表明CysLT 2 R负调控LTC 4S和CysLT 1 R依赖性DC介导的致敏。CysLT 2 R缺陷型BMDCs增加了CysLT 1 R依赖性LTD 4诱导的ERK磷酸化，而WT BMDCs上的CysLT 2 R的N-甲基LTC 4激活减少了这种信号传导。内源性表达的CysLT 1 R和CysLT 2 R的激活分别发生在LTD 4和N-甲基LTC 4的等摩尔范围内。尽管CysLT 2 R缺陷型BMDCs细胞表面CysLT 1 R的基线表达没有增加，但与WT或CysLT 2 R/LTC 4S缺陷型BMDCs相比，Df脉冲在24 h时上调。重要的是，用N-甲基LTC 4处理减少了WT BMDC上DF诱导的CysLT 1 R表达。因此，CysLT 2 R通过抑制CysLT 1 R信号传导和Df诱导的DC上CysLT 1 R的LTC 4S依赖性细胞表面表达来负调节cys-LT依赖性Th 2肺部炎症的发展。此外，这些研究强调了cys-LT的生物活性如何通过这些内源性表达的受体之间的竞争来严格调节。
Cysteinyl leukotrienes (cys-LTs) can mediate Th2 immunity to the house dust mite, Dermatophagoides farinae (Df), via the type 1 receptor CysLT1R on dendritic cells (DCs). However, the role of the homologous type 2 receptor CysLT2R in Th2 immunity is unknown. Df sensitization and challenge of CysLT2R-deficient mice showed a marked augmentation of eosinophilic pulmonary inflammation, serum IgE, and Th2 cytokines. Wild-type (WT) mice sensitized by adoptive transfer of Df-pulsed CysLT2R-deficient bone marrow-derived DCs (BMDCs) also had a marked increase in Df-elicited eosinophilic lung inflammation and Th2 cytokines in restimulated hilar nodes. This response was absent in mice sensitized with Df-pulsed BMDCs lacking leukotriene C4 synthase (LTC4S), CysLT1R, or both CysLT2R/LTC4S, suggesting that CysLT2R negatively regulates LTC4S- and CysLT1R-dependent DC-mediated sensitization. CysLT2R-deficient BMDCs had increased CysLT1R-dependent LTD4-induced ERK phosphorylation, whereas N-methyl LTC4 activation of CysLT2R on WT BMDCs reduced such signaling. Activation of endogenously expressed CysLT1R and CysLT2R occurred over an equimolar range of LTD4 and N-methyl LTC4, respectively. Although the baseline expression of cell surface CysLT1R was not increased on CysLT2R-deficient BMDCs, it was upregulated at 24 h by a pulse of Df, as compared to WT or CysLT2R/LTC4S-deficient BMDCs. Importantly, treatment with N-methyl LTC4 reduced Df-induced CysLT1R expression on WT BMDCs. Thus, CysLT2R negatively regulates the development of cys-LT-dependent Th2 pulmonary inflammation by inhibiting both CysLT1R signaling and Df-induced LTC4S-dependent cell surface expression of CysLT1R on DCs. Furthermore, these studies highlight how the biologic activity of cys-LTs can be tightly regulated by competition between these endogenously expressed receptors.
登录
查看更多内容
DOI：
10.1084/jem.20100793
发表时间：
2011-03-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Barrett NA;Rahman OM;Fernandez JM;Parsons MW;Xing W;Austen KF;Kanaoka Y
通讯作者：
Kanaoka Y
影响因子：
4.8
作者：
Maekawa, A;Austen, KF;Kanaoka, Y
通讯作者：
Kanaoka, Y
影响因子：
158.5
作者：
MANNING, PJ;WATSON, RM;OBYRNE, PM
通讯作者：
OBYRNE, PM
影响因子：
7.3
作者：
Benned-Jensen T;Rosenkilde MM
通讯作者：
Rosenkilde MM
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G