Universität zu Köln

Roderick, Justine E., Hermance, Nicole, Zelic, Matija, Simmons, Matthew J., Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kelliher, Michelle A. (2014). Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc. Natl. Acad. Sci. U. S. A., 111 (40). S. 14436 - 14442. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Roderick, Justine E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermance, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Simmons, Matthew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kelliher, Michelle A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-425880
DOI:	10.1073/pnas.1409389111
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	111
Number:	40
Page Range:	S. 14436 - 14442
Date:	2014
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RECEPTOR-INTERACTING PROTEIN; NECROSIS-FACTOR-ALPHA; DOMAIN KINASE RIP; FANCONI-ANEMIA PATIENTS; KAPPA-B ACTIVATION; CELL-DEATH; PROGRAMMED NECROSIS; TNF-ALPHA; PROGENITOR CELLS; APLASTIC-ANEMIA Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/42588