Dept. of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; School of Biosciences, Taylor's University, No 1, Jalan Taylor's, 47500, Subang Jaya, Selangor, Malaysia.
Dept. of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
Exp Parasitol. 2020 Sep;216:107946. doi: 10.1016/j.exppara.2020.107946. Epub 2020 Jul 2.
This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection.
本研究旨在探讨晚期糖基化终产物受体（RAGE）在疟疾感染过程中的作用，以及调节 RAGE 对疟原虫动物模型中炎症细胞因子释放和受影响器官组织病理学状况的影响。从感染后第 1 天至第 4 天，用 mRAGE/pAb 和 rmRAGE/Fc 嵌合体药物治疗感染 Plasmodium berghei（P. berghei）ANKA 的 ICR 小鼠。每天监测生存和寄生虫血症水平。在感染后第 5 天，处死小鼠，采集血液进行细胞因子分析，并提取肾脏、脾脏、肝脏、大脑和肺等主要器官进行组织病理学分析。在疟疾感染过程中，RAGE 水平在全身升高。观察到 RAGE 血浆浓度与寄生虫血症发展之间存在正相关。用 RAGE 相关药物治疗并未改善感染疟疾的小鼠的生存。然而，记录到寄生虫血症水平显著降低。另一方面，在感染过程中抑制和中和 RAGE 的产生显著增加了白细胞介素（IL-4、IL-17A、IL-10 和 IL-2）的血浆水平，并减少了干扰素（IFN）-γ的分泌。组织病理学分析显示，所有接受治疗的感染疟疾的小鼠在受影响器官（大脑、肝脏、脾脏、肺和肾脏）的组织学评估中表现出更好的结果。RAGE 参与疟疾发病机制，靶向 RAGE 可能对感染疟疾的宿主有益，其中 RAGE 抑制或中和增加了抗炎细胞因子（IL-10 和 IL-4）的释放，并减少了促炎细胞因子（IFNγ）的释放，这可能有助于减轻组织损伤并改善感染期间受影响器官的组织病理学状况。
