Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
Departments of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
J Leukoc Biol. 2023 May 2;113(5):471-488. doi: 10.1093/jleuko/qiad021.
Malaria infection causes multiple organ-specific lethal pathologies, including cerebral malaria, and severe liver and lung pathologies by inducing strong inflammatory responses. Gene polymorphism studies suggest that TLR4 and TLR2 contribute to severe malaria, but the roles of these signaling molecules in malaria pathogenesis remain incompletely understood. We hypothesize that danger-associated molecular patterns produced in response to malaria activate TLR2 and TLR4 signaling and contribute to liver and lung pathologies. By using a mouse model of Plasmodium berghei NK65 infection, we show that the combined TLR2 and TLR4 signaling contributes to malaria liver and lung pathologies and mortality. Macrophages, neutrophils, natural killer cells, and T cells infiltrate to the livers and lungs of infected wild-type mice more than TLR2,4-/- mice. Additionally, endothelial barrier disruption, tissue necrosis, and hemorrhage were higher in the livers and lungs of infected wild-type mice than in those of TLR2,4-/- mice. Consistent with these results, the levels of chemokine production, chemokine receptor expression, and liver and lung pathologic markers were higher in infected wild-type mice than in TLR2,4-/- mice. In addition, the levels of HMGB1, a potent TLR2- and TLR4-activating danger-associated molecular pattern, were higher in livers and lungs of wild-type mice than TLR2,4-/- mice. Treatment with glycyrrhizin, an immunomodulatory agent known to inhibit HMGB1 activity, markedly reduced mortality in wild-type mice. These results suggest that TLR2 and TLR4 activation by HMGB1 and possibly other endogenously produced danger-associated molecular patterns contribute to malaria liver and lung injury via signaling mechanisms distinct from those involved in cerebral malaria pathogenesis.
疟疾感染通过诱导强烈的炎症反应，导致多种器官特异性致命病变，包括脑型疟疾以及严重的肝和肺病变。基因多态性研究表明 TLR4 和 TLR2 有助于严重疟疾，但这些信号分子在疟疾发病机制中的作用仍不完全清楚。我们假设，疟疾引起的危险相关分子模式激活 TLR2 和 TLR4 信号通路，并导致肝和肺病变。通过使用 Plasmodium berghei NK65 感染的小鼠模型，我们表明 TLR2 和 TLR4 信号的联合作用导致疟疾肝和肺病变以及死亡率的增加。与 TLR2、4-/- 小鼠相比，感染野生型小鼠的肝脏和肺部有更多的巨噬细胞、中性粒细胞、自然杀伤细胞和 T 细胞浸润。此外，感染野生型小鼠的肝脏和肺部内皮屏障破坏、组织坏死和出血的程度高于 TLR2、4-/- 小鼠。与这些结果一致，感染野生型小鼠的趋化因子产生、趋化因子受体表达以及肝和肺病理标志物的水平均高于 TLR2、4-/- 小鼠。此外，HMGB1（一种有效的 TLR2 和 TLR4 激活危险相关分子模式）在野生型小鼠的肝脏和肺部的水平高于 TLR2、4-/- 小鼠。用甘草酸苷（一种已知抑制 HMGB1 活性的免疫调节剂）治疗可显著降低野生型小鼠的死亡率。这些结果表明，HMGB1 以及可能其他内源性产生的危险相关分子模式通过 TLR2 和 TLR4 的激活，通过与脑型疟疾发病机制不同的信号机制，导致疟疾肝和肺损伤。
