Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Laboratory of Applied Genetics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
PLoS One. 2018 Jun 14;13(6):e0199111. doi: 10.1371/journal.pone.0199111. eCollection 2018.
Hepatic dysfunction is one of the clinical features in severe malaria. However, the mechanism of hepatic injury during malaria is still unknown. Myeloid-related protein (MRP) 14 is abundantly expressed by myeloid cells and involved in various inflammatory diseases. We previously reported that serum MRP14 is elevated in mice infected with Plasmodium berghei ANKA. In order to verify whether extracellular MRP14 is involved in the pathology of hepatic injury during rodent malaria, we intravenously administrated recombinant MRP14 (rMRP14) to mice infected with P. berghei ANKA. The administration of rMRP14 did not affect parasite number or hematocrit. On the other hand, the hepatic injury was exacerbated in rMRP14-treated mice, and their serum concentration of hepatic enzymes increased significantly more than PBS-treated controls. Immunohistochemical analysis of the liver showed that more MRP14+ macrophages accumulated in rMRP14-treated mice than PBS-treated controls after infection. The administration of rMRP14 also promotes the up-regulation of pro-inflammatory molecules in the liver, such as iNOS, IL-1β, IL-12, and TNF-α. Even in the absence of Plasmodium infection, administration of rMRP14 could induce the accumulation of MRP14+ macrophages and up-regulation of the pro-inflammatory molecules in the liver of naïve mice. The results indicate that MRP14 promotes the accumulation of MRP14+ cells and the up-regulation of pro-inflammatory molecules and NO, which amplify inflammatory cascade leading to hepatic injury. In conclusion, MRP14 is a one of key molecules for liver inflammation during rodent malaria.
肝功能障碍是严重疟疾的临床特征之一。然而，疟疾期间肝损伤的机制尚不清楚。髓系相关蛋白 (MRP) 14 由髓系细胞大量表达，并参与各种炎症性疾病。我们之前报道过，感染疟原虫伯氏疟原虫 ANKA 的小鼠血清中 MRP14 升高。为了验证细胞外 MRP14 是否参与啮齿动物疟疾期间肝损伤的病理学，我们向感染疟原虫伯氏疟原虫 ANKA 的小鼠静脉内给予重组 MRP14 (rMRP14)。rMRP14 的给药并不影响寄生虫数量或血细胞比容。另一方面，rMRP14 处理的小鼠肝损伤加剧，其血清肝酶浓度明显高于 PBS 处理的对照组。肝的免疫组织化学分析表明，感染后 rMRP14 处理的小鼠比 PBS 处理的对照组中积聚了更多的 MRP14+巨噬细胞。rMRP14 的给药还促进了肝脏中促炎分子（如 iNOS、IL-1β、IL-12 和 TNF-α）的上调。即使在没有疟原虫感染的情况下，rMRP14 的给药也可诱导 MRP14+巨噬细胞的积聚和肝脏中促炎分子的上调。结果表明，MRP14 促进了 MRP14+细胞的积聚和促炎分子及 NO 的上调，放大了导致肝损伤的炎症级联反应。总之，MRP14 是啮齿动物疟疾期间肝脏炎症的关键分子之一。
