Extracellular adenosine controls NKT-cell-dependent hepatitis induction.
Extracellular adenosine controls NKT-cell-dependent hepatitis induction.
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DOI：
10.1002/eji.201343866
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发表时间：
2014-04
影响因子：
5.4
通讯作者：
Ohta, Akio
中科院分区：
文献类型：
--
作者：
Subramanian, Meenakshi;Kini, Radhika;Madasu, Manasa;Ohta, Akiko;Nowak, Michael;Exley, Mark;Sitkovsky, Michail;Ohta, Akio
细胞外腺苷通过A2 A腺苷受体（A2 AR）调节炎症反应。A2 AR缺乏导致严重急性肝炎，表明腺苷-A2 AR途径在免疫激活的抑制机制中不冗余。为了确定细胞外腺苷免疫调节作用的关键靶点，我们将重点放在NKT细胞上，NKT细胞在肝炎中起着不可或缺的作用。A2 AR激动剂可阻断Con A或α-半乳糖神经酰胺（α-GalCer）对NKT细胞依赖性急性肝炎的诱导作用，这与NKT细胞中活化标志物和细胞因子以及NK细胞共活化的下调相对应。这些结果表明，A2 AR信号可以下调NKT细胞活化并抑制NKT细胞触发的炎症反应。接下来，我们假设NKT细胞可能受腺苷-A2 AR通路的生理控制。事实上，Con A和α-GalCer在A2 AR −/−小鼠中诱导的肝炎比野生型对照更严重。将A2 AR −/− NKT细胞转移到表达A2 AR的受体中，导致Con A诱导的肝损伤加重，表明NKT细胞活化由内源性腺苷通过A2 AR控制，NKT细胞的这种生理调节机制在控制组织损伤性炎症中至关重要。目前的研究表明，通过干预腺苷-A2 AR通路来操纵炎症性疾病中NKT细胞活性的可能性。
Extracellular adenosine regulates inflammatory responses via A2A adenosine receptor (A2AR). A2AR-deficiency results in much exaggerated acute hepatitis, indicating non-redundancy of adenosine-A2AR pathway in inhibitory mechanisms of immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. A2AR agonist abolished NKT cell-dependent induction of acute hepatitis by Con A or α-galactosylceramide (α-GalCer), corresponding to down-regulation of activation markers and cytokines in NKT cells and of NK cell co-activation. These results show that A2AR signaling can down-regulate NKT cell activation and suppress NKT cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-GalCer induced more severe hepatitis in A2AR−/− mice than in wild-type controls. Transfer of A2AR−/− NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway.
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影响因子：
15.3
作者：
Kaneko, Y;Harada, M;Kawano, T;Yamashita, M;Shibata, Y;Gejyo, F;Nakayama, T;Taniguchi, M
通讯作者：
Taniguchi, M
DOI：
10.1084/jem.20061097
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lappas CM;Day YJ;Marshall MA;Engelhard VH;Linden J
通讯作者：
Linden J
影响因子：
7.3
作者：
Chan, Edwin S. L.;Montesinos, Maria Carmen;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.
影响因子：
6.7
作者：
Juno JA;Keynan Y;Fowke KR
通讯作者：
Fowke KR
DOI：
10.1056/nejmra1205750
发表时间：
2012-12-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eltzschig HK;Sitkovsky MV;Robson SC
通讯作者：
Robson SC