Universität zu Köln

Carnevalli, Larissa S., Scognamiglio, Roberta, Cabezas-Wallscheid, Nina, Rahmig, Susann, Laurenti, Elisa ORCID: 0000-0002-9917-9092, Masuda, Kohei, Joeckel, Lars, Kuck, Andrea, Sujer, Stefanie, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Erlacher, Miriam, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Essers, Marieke A. G. and Trumpp, Andreas ORCID: 0000-0002-6212-3466 (2014). Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B. J. Exp. Med., 211 (5). S. 769 - 780. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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Abstract

The serine protease granzyme B (GzmB) is stored in the granules of cytotoxic T and NK cells and facilitates immune-mediated destruction of virus-infected cells. In this study, we use genetic tools to report novel roles for GzmB as an important regulator of hematopoietic stem cell (HSC) function in response to stress. HSCs lacking the GzmB gene show improved bone marrow (BM) reconstitution associated with increased HSC proliferation and mitochondrial activity. In addition, recipients deficient in GzmB support superior engraftment of wild-type HSCs compared with hosts with normal BM niches. Stimulation of mice with lipopolysaccharide strongly induced GzmB protein expression in HSCs, which was mediated by the TLR4-TRIF-p65 NF-kappa B pathway. This is associated with increased cell death and GzmB secretion into the BM environment, suggesting an extracellular role of GzmB in modulating HSC niches. Moreover, treatment with the chemotherapeutic agent 5-fluorouracil (5-FU) also induces GzmB production in HSCs. In this situation GzmB is not secreted, but instead causes cell-autonomous apoptosis. Accordingly, GzmB-deficient mice are more resistant to serial 5-FU treatments. Collectively, these results identify GzmB as a negative regulator of HSC function that is induced by stress and chemotherapy in both HSCs and their niches. Blockade of GzmB production may help to improve hematopoiesis in various situations of BM stress.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Carnevalli, Larissa S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scognamiglio, Roberta UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabezas-Wallscheid, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahmig, Susann UNSPECIFIED UNSPECIFIED UNSPECIFIED Laurenti, Elisa UNSPECIFIED orcid.org/0000-0002-9917-9092 UNSPECIFIED Masuda, Kohei UNSPECIFIED UNSPECIFIED UNSPECIFIED Joeckel, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuck, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Sujer, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Erlacher, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Essers, Marieke A. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trumpp, Andreas UNSPECIFIED orcid.org/0000-0002-6212-3466 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-438546
DOI:	10.1084/jem.20131072
Journal or Publication Title:	J. Exp. Med.
Volume:	211
Number:	5
Page Range:	S. 769 - 780
Date:	2014
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-9538
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 HEMATOPOIETIC STEM-CELLS; VERSUS-HOST-DISEASE; SELF-RENEWAL; C-MYC; CLEAVAGE; FIBRONECTIN; MECHANISMS; LEUKOCYTES; INFECTION; SURVIVAL Multiple languages Immunology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/43854