Radiation exposure induces inflammasome pathway activation in immune cells.
Radiation exposure induces inflammasome pathway activation in immune cells.
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DOI：
10.4049/jimmunol.1303051
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发表时间：
2015-02-01
期刊：
影响因子：
--
通讯作者：
Lederer JA
中科院分区：
文献类型：
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作者：
Stoecklein VM;Osuka A;Ishikawa S;Lederer MR;Wanke-Jellinek L;Lederer JA
辐射可引起细胞和组织损伤，引起局部和全身炎症反应。由于炎症体途径是由细胞死亡和危险相关的分子模式(DAMP)触发的，我们假设炎症体可能发出辐射急性和慢性免疫反应的信号。使用小鼠辐射模型，我们发现辐射诱导巨噬细胞、树突状细胞、NK细胞、T细胞和B细胞中的炎症体激活呈剂量依赖性增加，这是通过细胞中caspase 1的裂解检测来判断的。时程分析显示，照射后第1天细胞内出现caspase 1裂解产物，并持续表达至第7天。此外，显示炎症体激活的细胞共表达细胞表面凋亡标记Annexin V。在Caspase1−/−小鼠中，研究了Caspase1作为辐射后造血细胞损失的触发因素的作用。我们发现在caspase1−/−小鼠中辐射诱导的细胞凋亡和免疫细胞丢失比对照小鼠要少。接下来，我们测试了尿酸是否可能通过用别嘌醇处理小鼠来介导细胞中的炎症体激活，并发现别嘌醇处理完全阻断了细胞中caspase 1的激活。最后，我们证明了辐射诱导的caspase1激活是通过节点样受体家族蛋白3(NLRP3)独立的机制发生的，因为辐射暴露的Nlrp3−/−小鼠表现出与野生型小鼠没有区别的caspase1激活特征。综上所述，我们的数据表明，在辐射暴露后，许多免疫细胞类型都会发生炎性小体激活，别嘌醇可以阻止辐射诱导的炎性小体激活。这些结果表明，靶向炎症小体可能有助于控制辐射引起的炎症。
Radiation exposure induces cell and tissue damage causing local and systemic inflammatory responses. Since the inflammasome pathway is triggered by cell death and danger-associated molecular patterns (DAMPs), we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase 1 detection in cells. Time course analysis showed the appearance of cleaved caspase 1 in cells by day 1 and sustained expression until day 7 post-radiation. Also, cells showing inflammasome activation co-expressed the cell-surface apoptosis marker, Annexin V. The role of caspase 1 as a trigger for hematopoietic cell losses after radiation was studied in caspase 1 −/− mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase 1 −/− mice than control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase 1 activation in cells. Finally, we demonstrate that radiation-induced caspase 1 activation occurs by a Nod-like receptor family protein 3 (NLRP3) independent mechanism since radiation-exposed Nlrp3 −/− mice showed caspase 1 activation profiles that were indistinguishable from wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation.
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