Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Am J Transplant. 2022 Jun;22(6):1578-1592. doi: 10.1111/ajt.17034. Epub 2022 Apr 4.
Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.
受损细胞释放的线粒体激活内皮细胞 (EC)，促进炎症过程，包括同种异体移植物排斥。干扰素基因刺激物 (STING) 感知内源性线粒体 DNA，通过 NF-κB 信号触发先天免疫激活。在这里，我们表明，外源性线粒体暴露诱导 EC STING-NF-κB 激活，促进 EC/效应记忆 T 细胞黏附，NF-κB 和 STING 抑制剂可阻断该过程。线粒体激活的 EC 中的 STING 激活不依赖于经典的 cGMP-AMP 合酶感应/信号转导，而是由干扰素 γ诱导因子 16 (IFI16) 介导，IFI16 抑制可抑制其作用。内化的线粒体经历线粒体融合和 STING 依赖性线粒体自噬，导致内化线粒体的选择性隔离。供体心脏暴露于外源性线粒体可在体内激活小鼠心脏 EC。总的来说，我们的结果表明，IFI16-STING-NF-κB 信号通路调节外源性线粒体诱导的 EC 激活和线粒体自噬，外源性线粒体促进 T 细胞介导的 CoBRR。这些数据表明了一种新的、供体定向的治疗方法，可减轻围手术期同种异体移植物免疫原性。
