Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis
| Autor: | Manolis Pasparakis, Matija Zelic, Justine E. Roderick, Apostolos Polykratis, Matthew J. Simmons, Nicole Hermance, Michelle A. Kelliher |
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| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
Necroptosis Apoptosis Mice Transgenic Thymus Gland Biology Proinflammatory cytokine RIPK1 Necrosis Bone Marrow medicine Animals Progenitor cell Intestinal Mucosa Cells Cultured Mice Knockout Multidisciplinary Tumor Necrosis Factor-alpha Estrogen Antagonists Epithelial Cells Biological Sciences Flow Cytometry Hematopoietic Stem Cells Mice Inbred C57BL Haematopoiesis Tamoxifen medicine.anatomical_structure Receptor-Interacting Protein Serine-Threonine Kinases Cancer research Cytokines Bone marrow Inflammation Mediators Spleen |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 111(40) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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