Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
J Immunol. 2012 Jul 15;189(2):906-15. doi: 10.4049/jimmunol.1200257. Epub 2012 Jun 13.
Pattern recognition receptors for fungi include dectin-1 and mannose receptor, and these mediate phagocytosis, as well as production of cytokines, reactive oxygen species, and the lipid mediator leukotriene B(4) (LTB(4)). The influence of G protein-coupled receptor ligands such as LTB(4) on fungal pattern recognition receptor expression is unknown. In this study, we investigated the role of LTB(4) signaling in dectin-1 expression and responsiveness in macrophages. Genetic and pharmacologic approaches showed that LTB(4) production and signaling through its high-affinity G protein-coupled receptor leukotriene B(4) receptor 1 (BLT1) direct dectin-1-dependent binding, ingestion, and cytokine production both in vitro and in vivo. Impaired responses to fungal glucans correlated with lower dectin-1 expression in macrophages from leukotriene (LT)- and BLT1-deficent mice than their wild-type counterparts. LTB(4) increased the expression of the transcription factor responsible for dectin-1 expression, PU.1, and PU.1 small interfering RNA abolished LTB(4)-enhanced dectin-1 expression. GM-CSF controls PU.1 expression, and this cytokine was decreased in LT-deficient macrophages. Addition of GM-CSF to LT-deficient cells restored expression of dectin-1 and PU.1, as well as dectin-1 responsiveness. In addition, LTB(4) effects on dectin-1, PU.1, and cytokine production were blunted in GM-CSF(-/-) macrophages. Our results identify LTB(4)-BLT1 signaling as an unrecognized controller of dectin-1 transcription via GM-CSF and PU.1 that is required for fungi-protective host responses.
真菌的模式识别受体包括 dectin-1 和甘露糖受体，它们介导吞噬作用以及细胞因子、活性氧物种和脂质介质白三烯 B4（LTB4）的产生。G 蛋白偶联受体配体（如 LTB4）对真菌模式识别受体表达的影响尚不清楚。在这项研究中，我们研究了 LTB4 信号在巨噬细胞中 dectin-1 表达和反应性中的作用。遗传和药理学方法表明，LTB4 的产生和通过其高亲和力 G 蛋白偶联受体白三烯 B4 受体 1（BLT1）的信号传导直接指导体外和体内 dectin-1 依赖性结合、摄取和细胞因子产生。与野生型相比，缺乏白细胞三烯（LT）和 BLT1 的巨噬细胞对真菌葡聚糖的反应受损，与 dectin-1 表达降低相关。LTB4 增加了负责 dectin-1 表达的转录因子 PU.1 的表达，而 PU.1 小干扰 RNA 则消除了 LTB4 增强的 dectin-1 表达。GM-CSF 控制 PU.1 的表达，而这种细胞因子在 LT 缺陷型巨噬细胞中减少。向 LT 缺陷型细胞中添加 GM-CSF 可恢复 dectin-1 和 PU.1 的表达以及 dectin-1 的反应性。此外，LTB4 对 dectin-1、PU.1 和细胞因子产生的作用在 GM-CSF（-/-）巨噬细胞中减弱。我们的结果表明，LTB4-BLT1 信号通过 GM-CSF 和 PU.1 作为未被识别的 dectin-1 转录控制器，这对于宿主对真菌的保护反应是必需的。
