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Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B
- Source :
- The Journal of Experimental Medicine, Journal of Experimental Medicine
- Publication Year :
- 2014
- Publisher :
- Rockefeller University Press, 2014.
-
Abstract
- Granzyme B is expressed by hematopoietic stem cells (HSCs) and stromal cells in response to bacterial products or chemotherapy agents and limits HSC reconstitution potential.<br />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.
- Subjects :
- Lipopolysaccharides
Programmed cell death
Immunology
Apoptosis
Enzyme-Linked Immunosorbent Assay
Real-Time Polymerase Chain Reaction
Granzymes
GZMB
Colony-Forming Units Assay
Mice
Drug Therapy
Bone Marrow
Stress, Physiological
medicine
Immunology and Allergy
Cytotoxic T cell
Animals
Cell Proliferation
DNA Primers
Mice, Knockout
biology
Brief Definitive Report
Hematopoietic stem cell
hemic and immune systems
Flow Cytometry
Hematopoietic Stem Cells
Microarray Analysis
Immunohistochemistry
Cell biology
Mitochondria
Granzyme B
Mice, Inbred C57BL
Haematopoiesis
medicine.anatomical_structure
Granzyme
Gene Expression Regulation
biology.protein
Bone marrow
Fluorouracil
Signal Transduction
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine, Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....f6f6cbcae0639c921b34df83f83ccb31