Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
PLoS Pathog. 2013 May;9(5):e1003351. doi: 10.1371/journal.ppat.1003351. Epub 2013 May 9.
Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic protein that plays a defensive role in bacterial infection by sensing peptidoglycans. C5a, which has harmful effects in sepsis, interacts with innate proteins. However, whether NOD2 regulates C5a generation during sepsis remains to be determined. To address this issue, cecal ligation & puncture (CLP)-induced sepsis was compared in wild type and Nod2-/- mice. Nod2-/- mice showed lower levels of C5a, IL-10, and IL-1β in serum and peritoneum, but higher survival rate during CLP-induced sepsis compared to wild type mice. Injection of recombinant C5a decreased survival rates of Nod2-/- mice rate during sepsis, whereas it did not alter those in wild type mice. These findings suggest a novel provocative role for NOD2 in sepsis, in contrast to its protective role during bacterial infection. Furthermore, we found that NOD2-mediated IL-10 production by neutrophils enhanced C5a generation by suppressing CD55 expression on neutrophils in IL-1β-dependent and/or IL-1β-independent manners, thereby aggravating CLP-induced sepsis. SB203580, a receptor-interacting protein 2 (RIP2) inhibitor downstream of NOD2, reduced C5a generation by enhancing CD55 expression on neutrophils, resulting in attenuation of polymicrobial sepsis. Therefore, we propose a novel NOD2-mediated complement cascade regulatory pathway in sepsis, which may be a useful therapeutic target.
核苷酸结合寡聚化结构域（NOD）2 是一种细胞溶质蛋白，通过感知肽聚糖在细菌感染中发挥防御作用。C5a 在败血症中具有有害作用，与先天蛋白相互作用。然而，NOD2 是否调节败血症期间的 C5a 产生仍有待确定。为了解决这个问题，比较了野生型和 Nod2-/-小鼠的盲肠结扎和穿刺（CLP）诱导的败血症。与野生型小鼠相比，Nod2-/-小鼠在 CLP 诱导的败血症期间血清和腹膜中 C5a、IL-10 和 IL-1β 的水平较低，但存活率较高。重组 C5a 的注射降低了败血症期间 Nod2-/-小鼠的存活率，而对野生型小鼠没有影响。这些发现表明 NOD2 在败血症中具有新的促炎作用，与细菌感染期间的保护作用相反。此外，我们发现 NOD2 介导的中性粒细胞产生的 IL-10 通过抑制中性粒细胞上 CD55 的表达来增强 C5a 的产生，从而加重 CLP 诱导的败血症，这种作用依赖于或不依赖于 IL-1β。NOD2 下游的受体相互作用蛋白 2（RIP2）抑制剂 SB203580 通过增强中性粒细胞上 CD55 的表达来减少 C5a 的产生，从而减轻多微生物败血症。因此，我们提出了一种新的 NOD2 介导的败血症补体级联调节途径，它可能是一个有用的治疗靶点。
