title: Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B.
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-κB 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.
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), D-69120 Heidelberg, Germany.
authors.forename: Larissa S
authors.initials: LS
authors.lastname: Carnevalli
authors.forename: Roberta
authors.initials: R
authors.lastname: Scognamiglio
authors.forename: Nina
authors.initials: N
authors.lastname: Cabezas-Wallscheid
authors.forename: Susann
authors.initials: S
authors.lastname: Rahmig
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.forename: Kohei
authors.initials: K
authors.lastname: Masuda
authors.forename: Lars
authors.initials: L
authors.lastname: Jöckel
authors.forename: Andrea
authors.initials: A
authors.lastname: Kuck
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sujer
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Marieke A G
authors.initials: MA
authors.lastname: Essers
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000235:genetics; D004358:Drug Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D053804:Granzymes / Q000172:deficiency / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D017931:DNA Primers; D008070:Lipopolysaccharides; D053804:Granzymes; D005472:Fluorouracil
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