title: Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis.
abstract: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is recruited to the TNF receptor 1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. RIPK1 deficiency results in postnatal lethality, but precisely why Ripk1(-/-) mice die remains unclear. To identify the lineages and cell types that depend on RIPK1 for survival, we generated conditional Ripk1 mice. Tamoxifen administration to adult RosaCreER(T2)Ripk1(fl/fl) mice results in lethality caused by cell death in the intestinal and hematopoietic lineages. Similarly, Ripk1 deletion in cells of the hematopoietic lineage stimulates proinflammatory cytokine and chemokine production and hematopoietic cell death, resulting in bone marrow failure. The cell death reflected cell-intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, because Vav-iCre Ripk1(fl/fl) fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. We demonstrate that RIPK3 deficiency partially rescues hematopoiesis in Vav-iCre Ripk1(fl/fl) mice, showing that RIPK1-deficient hematopoietic cells undergo RIPK3-mediated necroptosis. However, the Vav-iCre Ripk1(fl/fl) Ripk3(-/-) progenitors remain TNF sensitive in vitro and fail to repopulate irradiated mice. These genetic studies reveal that hematopoietic RIPK1 deficiency triggers both apoptotic and necroptotic death that is partially prevented by RIPK3 deficiency. Therefore, RIPK1 regulates hematopoiesis and prevents inflammation by suppressing RIPK3 activation.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Justine E
authors.initials: JE
authors.lastname: Roderick
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Nicole
authors.initials: N
authors.lastname: Hermance
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Matija
authors.initials: M
authors.lastname: Zelic
authors.affiliation: BIND Biosciences, Inc., Cambridge, MA 02139; and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Simmons
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; Michelle.Kelliher@umassmed.edu.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004965:Estrogen Antagonists; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse
keywords: hematopoietic failure; programmed necrosis; tumor necrosis factor