Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors
Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors
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DOI：
10.1038/cdd.2014.178
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发表时间：
2015-04-01
影响因子：
12.4
通讯作者：
Schattenberg, J. M.
中科院分区：
文献类型：
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作者：
Gehrke, N.;Garcia-Bardon, D.;Schattenberg, J. M.
细胞凋亡信号通路既参与生理组织稳态，也参与急慢性疾病。调控细胞凋亡信号分子的作用及其器官特异性功能尚不明确。因此，我们利用诱导型敲除小鼠研究了抗凋亡细胞flice抑制蛋白（cFLIP）的缺失以及由此导致的体内致命器官衰竭的机制。这些是通过将固定的cFLIP小鼠与他莫昔芬诱导的Rosa26-creERT2小鼠株杂交产生的。由于肝功能衰竭、m1极化巨噬细胞的积累以及伴随的肝细胞死亡和炎症，导致了cFLIP整体丧失后的死亡。细胞凋亡在免疫细胞、肾上皮细胞和肠上皮细胞（IECs）中也很突出，但在心肌细胞中不明显。细胞损伤导致损伤相关分子模式（DAMPs）的释放和先天免疫受体的诱导，包括toll样受体（TLRs） 4和9，以及干扰素基因刺激因子（STING）。用完整的cFLIP或巨噬细胞清除骨髓移植可预防急性肝衰竭的表型。有趣的是，骨髓源性细胞和肝细胞中cFLIP的复合缺失并不会促进器官衰竭。因此，cFLIP通过阻止单核细胞和先天免疫的激活，从而在易感组织中引起细胞死亡和炎症，从而在组织稳态中发挥关键作用。这些结果促进了急性器官衰竭中器官特异性抗凋亡和抗炎治疗的发展。
Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.