Abstract：
Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.
摘要：
经过训练的免疫在机械上被定义为先天免疫系统的代谢和表观遗传介导的长期功能适应。以对二次刺激的反应增强为特征。给定适当的激活，经过训练的免疫力是一个有吸引力的抗感染治疗靶点。然而，过度的免疫反应和随后的炎症级联反应可能导致病理组织损伤，表明受过训练的免疫力的负面影响似乎是显著的。在这项研究中,我们表明，先天免疫反应，如细胞外陷阱的产生，促炎细胞因子，和自噬相关蛋白在训练过的BMDMs中显著增强。此外，热抑制白色念珠菌引发促进AIM2炎性体的激活，和AIM2-/-小鼠表现出热灭活白色念珠菌诱导的记忆反应受损。因此,我们确定AIM2炎性体参与经过训练的免疫,并成为潜在有害作用的有希望的治疗靶点.双氢青蒿素可以通过调节mTOR信号和AIM2炎性体来抑制热灭活白色念珠菌诱导的记忆反应。结果表明，双氢青蒿素可以降低C57BL/6小鼠中热灭活白色念珠菌对训练免疫的诱导。双氢青蒿素是一种这样的治疗干预措施,其具有治疗以过度训练的免疫力为特征的疾病的潜力。
