Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg, Germany.
Cells. 2023 Dec 20;13(1):16. doi: 10.3390/cells13010016.
Clinical islet transplantation is limited by ischemia-induced islet cell death. Recently, it has been reported that the absent in melanoma (AIM)2 inflammasome is upregulated by ischemic cell death due to recognition of aberrant cytoplasmic self-dsDNA. However, it is unknown whether AIM2 determines the outcome of islet transplantation. To investigate this, isolated wild type (WT) and -deficient () islets were exposed to oxygen-glucose deprivation to mimic ischemia, and their viability, endocrine function, and interferon (IFN) signaling were assessed. Moreover, the revascularization and endocrine function of grafted WT and islets were analyzed in the mouse dorsal skinfold chamber model and the diabetic kidney capsule model. Ischemic WT and islets did not differ in their viability. However, islets exhibited a higher protein level of p202, a transcriptional regulator of IFN-β and IFN-γ gene expression. Accordingly, these cytokines were upregulated in islets, resulting in a suppressed gene expression and secretion of insulin. Moreover, the revascularization of islet grafts was deteriorated when compared to WT controls. Furthermore, transplantation of islets in diabetic mice failed to restore physiological blood glucose levels. These findings indicate that AIM2 crucially determines the engraftment and endocrine function of transplanted islets by repressing IFN signaling.
临床胰岛移植受到缺血诱导的胰岛细胞死亡的限制。最近有报道称，黑色素瘤缺失（AIM）2 炎症小体由于识别异常细胞质自身 dsDNA 而被缺血性细胞死亡上调。然而，尚不清楚 AIM2 是否决定胰岛移植的结果。为了研究这一点，分离野生型（WT）和 -缺陷（）胰岛暴露于氧葡萄糖剥夺以模拟缺血，并评估其活力、内分泌功能和干扰素（IFN）信号。此外，在小鼠背部皮褶室模型和糖尿病肾囊模型中分析了移植的 WT 和 胰岛的再血管化和内分泌功能。缺血性 WT 和 胰岛在其活力上没有差异。然而， 胰岛表现出更高水平的 p202，IFN-β 和 IFN-γ 基因表达的转录调节剂。因此，这些细胞因子在上调，导致胰岛素的基因表达和分泌受到抑制。此外，与 WT 对照相比， 胰岛移植物的再血管化恶化。此外，将 胰岛移植到糖尿病小鼠中未能恢复生理血糖水平。这些发现表明，AIM2 通过抑制 IFN 信号来决定移植胰岛的植入和内分泌功能。
