Details

Autor(en) / Beteiligte

• Rickard, James A.
• O’Donnell, Joanne A.
• Evans, Joseph M.
• Lalaoui, Najoua
• Poh, Ashleigh R.
• Rogers, TeWhiti
• Vince, James E.
• Lawlor, Kate E.
• Ninnis, Robert L.
• Anderton, Holly
• Hall, Cathrine
• Spall, Sukhdeep K.
• Phesse, Toby J.
• Abud, Helen E.
• Cengia, Louise H.
• Corbin, Jason
• Mifsud, Sandra
• Di Rago, Ladina
• Metcalf, Donald
• Ernst, Matthias
• Dewson, Grant
• Roberts, Andrew W.
• Alexander, Warren S.
• Murphy, James M.
• Ekert, Paul G.
• Masters, Seth L.
• Vaux, David L.
• Croker, Ben A.
• Gerlic, Motti
• Silke, John

Titel

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

Ist Teil von

• Cell, 2014-05, Vol.157 (5), p.1175-1188

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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. [Display omitted] •RIPK1 delivers a TNF-dependent survival signal to HSC entering the bone marrow•RIPK1 can inhibit RIPK3/MLKL necroptosis•RIPK3/MLKL-dependent necroptosis causes IL-33 release in Ripk1−/− mice•Lethal, necroptosis-induced, systemic inflammation in Ripk1−/− mice is Myd88 dependent Ripk1 deficiency induces RIPK3/MLKL-dependent necroptosis, triggers IL-33 release, and causes Myd88-dependent systemic inflammation and perinatal death. These phenotypes could be rescued by deletion of Ripk3 and Casp8, revealing a key function for RIPK1 in inhibiting necroptosis and limiting inflammation.