Goodridge Helen S, Shimada Takahiro, Wolf Andrea J, Hsu Yen-Michael S, Becker Courtney A, Lin Xin, Underhill David M
Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
J Immunol. 2009 Jan 15;182(2):1146-54. doi: 10.4049/jimmunol.182.2.1146.
The pattern recognition receptors TLR2 and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of proinflammatory cytokines is instructed by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-kappaB and proinflammatory cytokine induction in murine bone marrow-derived DC stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-kappaB and drive TNF-alpha induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-gamma permits Dectin-1-CARD9-mediated TNF-alpha induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-alpha production. Resident peritoneal cells and alveolar macrophages produce TNF-alpha upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9, and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-alpha induction.
模式识别受体TLR2和Dectin-1在协调巨噬细胞和树突状细胞（DC）对真菌的反应中起关键作用。促炎细胞因子的诱导由来自TLR2和Dectin-1的信号指导。最近的一份报告确定了CARD9在先天性抗真菌反应中的作用，证明了在通过Dectin-1刺激的小鼠骨髓来源的DC中，CARD9-Bcl10介导的NF-κB激活和促炎细胞因子诱导。我们现在报告，在小鼠骨髓来源的巨噬细胞中，Dectin-1-CARD9信号未能激活NF-κB并驱动TNF-α诱导。然而，用GM-CSF或IFN-γ对骨髓来源的巨噬细胞进行预处理可使Dectin-1-CARD9介导TNF-α诱导。对其他巨噬细胞/DC群体的分析揭示了Dectin-1-CARD9信号驱动TNF-α产生能力的进一步差异。驻留腹膜细胞和肺泡巨噬细胞在Dectin-1连接后产生TNF-α，而巯基乙酸诱导的腹膜巨噬细胞和Flt3L来源的DC则不产生。我们提供的数据表明，CARD9通过其CARD结构域被招募到吞噬体，在那里它增强了TLR诱导的细胞因子产生，即使在Dectin-1不足以驱动细胞因子产生的细胞中也是如此。在这些细胞中，Dectin-1、CARD9和Bcl10的水平并不受限，数据表明这些细胞表达额外的因子，这些因子限制了Dectin-1-CARD9信号对TNF-α诱导的作用。
