RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
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DOI：
10.1016/j.cell.2014.04.019
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发表时间：
2014-05-22
期刊：
影响因子：
64.5
通讯作者：
Silke, John
中科院分区：
文献类型：
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作者：
Rickard, James A.;O'Donnell, Joanne A.;Silke, John
与配体结合后，RIPK1被招募为肿瘤坏死因子受体超家族(TNFRSF)和Toll样受体(TLR)复合体，促进生存和炎症信号转导。RIPK1还直接调节caspase-8介导的细胞凋亡，或者，如果caspase-8活性被阻断，RIPK3-MLKL依赖的坏死性下垂。我们发现，C57BL/6 Ripk1(-/-)小鼠出生时就死于不能通过造血室转移的全身炎症。然而，Ripk1(-/-)祖细胞未能正确地植入致死性照射的宿主。阻断肿瘤坏死因子逆转了紧急造血中的这一缺陷，但令人惊讶的是，Tnfr1缺乏并不能预防Ripk1(-/-)新生儿的炎症。RIPK3或MLKL的缺失，而不是Casp8的缺失，阻止了细胞外坏死性潮湿IL-33的释放，并减少了MyD88依赖的炎症。Ripk1(-/-)RIPK3(-/-)、Ripk1(-/-)MLKL(-/-)和Ripk1(-/-)MyD88(-/-)小鼠的炎症减少防止了新生儿死亡，但只有Ripk1(-/-)RIPK3(-/-)Casp8(-/-)小鼠在断奶后存活。这些结果揭示了RIPK1在抑制坏死性下垂中的关键作用，从而在限制而不仅仅是促进炎症方面发挥了作用。
Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-) Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.