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Title: Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis
Authors: Sánchez, Ángela
Relaño, Carlos
Carrasco, Araceli
Contreras-Jurado, Constanza
Martin-Duce, Antonio
Aranda, Ana
Alemany, Susana
UNESCO Clasification: 32 Ciencias médicas
Keywords: Hematopoietic Progenitor Cells
Toll-Like Receptors
Myeloid Progenitor
Pathogen Signals
Tpl2 Kinase
Issue Date: 2017
Journal: Scientific Reports 
Abstract: Map3k8 has been proposed as a useful target for the treatment of inflammatory diseases. We show here that during lipopolysaccharide-induced emergency granulopoiesis, Map3k8 deficiency strongly impairs the increase in circulating mature (Ly6G(high)CD11b(+)) and immature (Ly6G(low)CD11b(+)) neutrophils. After chimaeric bone marrow (BM) transplantation into recipient Map3k8(-/-) mice, lipopolysaccharide treatment did not increase circulating Ly6G(high)CD11b(+) cells and strongly decreased circulating Ly6G(low)CD11b(+) cells. Lipopolysaccharide-treated Map3k8(-/-) mice showed decreased production of granulocyte colony-stimulating factor (G-CSF), a key factor in neutrophil expansion, and a Map3k8 inhibitor blocked lipopolysaccharide-mediated G-CSF expression in endothelial cell lines. Ly6G(low)CD11b(+) BM cells from lipopolysaccharide-treated Map3k8(-/-) mice displayed impaired expression of CCAAT-enhancer-binding protein beta, which depends on G-CSF for expression and is crucial for cell cycle acceleration in this life-threatening condition. Accordingly, lipopolysaccharide-treated Map3k8(-/-) mice showed decreased Ly6G(low)CD11b(+) BM cell proliferation, as evidenced by a decrease in the percentage of the most immature precursors, which have the highest proliferation capacity among this cell population. Thus, Map3k8 expression by non-haematopoietic tissue is required for lipopolysaccharide-induced emergency granulopoiesis. The novel observation that inhibition of Map3k8 activity decreases neutrophilia during life-threatening systemic infection suggests a possible risk in the proposed use of Map3k8 blockade as an anti-inflammatory therapy.
ISSN: 2045-2322
DOI: 10.1038/s41598-017-04538-3
Source: Scientific Reports [ISSN 2045-2322], v. 7, article number 5010
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