Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 40, Pages 14436-14441Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1409389111
Keywords
tumor necrosis factor; programmed necrosis; hematopoietic failure
Categories
Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [AI075118]
- European Research Council [2012-ADG_20120314]
- Deutsche Forschungsgemeinschaft [SFB670, SFB829, SPP1656]
- European Commission Seventh Framework Program for Research and Technological Development [223404, 223151]
- Deutsche Krebshilfe Grant [110302]
- American Cancer Society [125087-PF-13-247-01-LIB]
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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.
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