Werts Catherine, le Bourhis Lionel, Liu Jianguo, Magalhaes Joao G, Carneiro Leticia A, Fritz Jörg H, Stockinger Silvia, Balloy Viviane, Chignard Michel, Decker Thomas, Philpott Dana J, Ma Xiaojing, Girardin Stephen E
Unité de Recherche Réponses Précoces aux Parasites et Immunopathologie, Institut Pasteur, Paris, France.
Eur J Immunol. 2007 Sep;37(9):2499-508. doi: 10.1002/eji.200737069.
The Nod-like receptor proteins Nod1 and Nod2 participate in innate immune responses against bacteria through intracellular detection of peptidoglycan, a component of bacterial cell wall. Recent evidence has demonstrated that Nod1 stimulates the release of chemokines that attract neutrophils at the site of infection, such as CXCL8/IL-8 in humans, and CXCL1/keratinocyte-derived chemokine and CXCL2/MIP-2 in mice. We aimed to determine whether Nod proteins could trigger the release of CCL5/RANTES, a chemokine known to attract a number of immune cells, but not neutrophils. Our results demonstrate that activation of both Nod1 and Nod2 results in substantial secretion of CCL5 by murine macrophages. Moreover, in vivo, the intraperitoneal injection of murine Nod1 or Nod2 agonists resulted in a rapid secretion of CCL5 into the bloodstream. We also observed that Nod-dependent secretion of CCL5 did not correlate with the induction of the interferon-beta pathway, a major signaling cascade for the activation of CCL5 by viruses. In contrast, we identified a key role of the NF-kappaB pathway in Nod-dependent stimulation of the CCL5 promoter. Together, these results identify a novel target downstream of Nod1 and Nod2, which is likely to play a key role in orchestrating the global Nod-dependent immune defense during bacterial infections.
核苷酸结合寡聚化结构域样受体蛋白Nod1和Nod2通过在细胞内检测肽聚糖（细菌细胞壁的一种成分）参与针对细菌的先天性免疫反应。最近的证据表明，Nod1刺激趋化因子的释放，这些趋化因子在感染部位吸引中性粒细胞，如人类中的CXCL8/IL-8，以及小鼠中的CXCL1/角质形成细胞衍生趋化因子和CXCL2/MIP-2。我们旨在确定Nod蛋白是否能触发CCL5/RANTES的释放，CCL5/RANTES是一种已知能吸引多种免疫细胞但不能吸引中性粒细胞的趋化因子。我们的结果表明，Nod1和Nod2的激活都会导致小鼠巨噬细胞大量分泌CCL5。此外，在体内，腹腔注射小鼠Nod1或Nod2激动剂会导致CCL5迅速分泌到血液中。我们还观察到，Nod依赖性的CCL5分泌与干扰素-β途径的诱导无关，干扰素-β途径是病毒激活CCL5的主要信号级联反应。相反，我们确定了NF-κB途径在Nod依赖性刺激CCL5启动子中的关键作用。总之，这些结果确定了Nod1和Nod2下游的一个新靶点，该靶点可能在细菌感染期间协调全局Nod依赖性免疫防御中发挥关键作用。
