RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis

Summary 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 Casp 8, 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.