Zhu Minghua, Barbas Andrew S, Lin Liwen, Scheuermann Uwe, Bishawi Muath, Brennan Todd V
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Immunohorizons. 2018 Dec;2(11):384-397. doi: 10.4049/immunohorizons.1800063.
In solid organ transplantation, cell death arising from ischemia/reperfusion leads to the release of several damage-associated molecular patterns derived from mitochondria. Mitochondrial damage-associated molecular patterns (mtDAMPs) initiate proinflammatory responses, but it remains unknown whether the mode of cell death affects the inflammatory properties of mitochondria. Murine and human cell lines induced to selectively undergo apoptosis and necroptosis were used to examine the extracellular release of mitochondria during programmed cell death. Mitochondria purified from healthy, apoptotic, and necroptotic cells were used to stimulate macrophage inflammasome responses in vitro and neutrophil chemotaxis in vivo. Inhibition of specific mtDAMPs was performed to identify those responsible for macrophage inflammasome activation. A rat liver transplant model was used to identify apoptotic and necroptotic cell death in graft tissue following ischemia/reperfusion. Both apoptotic and necroptotic cell death occur in parallel in graft tissue. Apoptotic cells released more mitochondria than necroptotic cells. Moreover, mitochondria from apoptotic cells were significantly more inflammatory in terms of macrophage inflammasome activation and neutrophil recruitment. Inhibition of cellular synthesis of cardiolipin, a mitochondria-specific lipid and mtDAMP, significantly reduced the inflammasome-activating properties of apoptosis-derived mitochondria. Mitochondria derived from apoptotic cells are potent activators of innate immune responses, whereas mitochondria derived from healthy or necroptotic cells are significantly less inflammatory. Cardiolipin appears to be a key mtDAMP-regulating inflammasome activation by mitochondria. Methods of inhibiting apoptotic cell death in transplant grafts may be beneficial for reducing graft inflammation and transplant allosensitization.
在实体器官移植中，缺血/再灌注引起的细胞死亡会导致多种源自线粒体的损伤相关分子模式的释放。线粒体损伤相关分子模式（mtDAMPs）引发促炎反应，但细胞死亡方式是否影响线粒体的炎症特性仍不清楚。利用诱导选择性发生凋亡和坏死性凋亡的小鼠和人类细胞系，来检测程序性细胞死亡过程中线粒体的细胞外释放。从健康、凋亡和坏死性凋亡细胞中纯化的线粒体，用于体外刺激巨噬细胞炎性小体反应和体内中性粒细胞趋化性。通过抑制特定的mtDAMPs来确定那些负责巨噬细胞炎性小体激活的分子。使用大鼠肝移植模型来识别缺血/再灌注后移植组织中的凋亡和坏死性凋亡细胞死亡。凋亡和坏死性凋亡细胞死亡在移植组织中同时发生。凋亡细胞释放的线粒体比坏死性凋亡细胞更多。此外，就巨噬细胞炎性小体激活和中性粒细胞募集而言，凋亡细胞的线粒体具有明显更强的炎症性。抑制心磷脂（一种线粒体特异性脂质和mtDAMP）的细胞合成，可显著降低凋亡来源线粒体的炎性小体激活特性。凋亡细胞来源的线粒体是先天免疫反应的有效激活剂，而健康或坏死性凋亡细胞来源的线粒体炎症性明显较弱。心磷脂似乎是线粒体调节炎性小体激活的关键mtDAMP。抑制移植移植物中凋亡细胞死亡的方法可能有助于减少移植物炎症和移植同种致敏。
