Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP-Avenida Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo 14049-900, Brazil.
Institute of Biomedical Science IV-University of São Paulo (USP), São Paulo, São Paulo 14049-900, Brazil.
Cells. 2020 Apr 14;9(4):959. doi: 10.3390/cells9040959.
Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2 mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2 mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.
模式识别受体（PRRs），如 Nod2、Nlrp3、Tlr2、Trl4 和 Tlr9，直接参与 1 型糖尿病（T1D）的易感性。然而，细胞质 DNA 传感器 AIM2 在 T1D 发病机制中的作用尚不清楚。在这里，我们证明与 WT C57BL/6 小鼠相比，缺乏 AIM2（AIM2）的 C57BL/6 小鼠易患链脲佐菌素（STZ）诱导的 T1D。AIM2 小鼠表型与胰腺组织中促炎反应增强、肠道微生物群改变以及细菌易位至胰腺淋巴结（PLN）有关。这些改变与紧密连接破坏介导的肠道通透性增加有关。值得注意的是，用广谱抗生素（ABX）治疗的 AIM2 小鼠可预防 STZ 诱导的 T1D，并显示较低的胰腺促炎反应。从机制上讲，AIM2 炎性小体在体内被激活，导致 STZ 注射后 15 天回肠中 IL-18 的释放。IL-18 有利于 RegIIIγ 的产生，从而减轻肠道微生物群的改变并增强肠道屏障功能。总之，我们的研究结果表明，AIM2 通过 IL-18 发挥调节作用，可塑造肠道微生物群并减少细菌易位和针对胰岛素产生β细胞的促炎反应，从而在 STZ 诱导的糖尿病模型中预防 T1D 的发生。
