Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis.

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 (Ly6GCD11b) and immature (Ly6GCD11b) neutrophils. After chimaeric bone marrow (BM) transplantation into recipient Map3k8 mice, lipopolysaccharide treatment did not increase circulating Ly6GCD11b cells and strongly decreased circulating Ly6GCD11b 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. Ly6GCD11b 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 Ly6GCD11b 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.