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标题：Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis
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作者：Ángela Sánchez ; Carlos Relaño ; Araceli Carrasco 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2017
卷号：7
期号：1
DOI：10.1038/s41598-017-04538-3
语种：English
出版社：Springer Nature
摘要：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 β, 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.