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 (Ly6GhighCD11b+) and immature (Ly6GlowCD11b+) neutrophils. After chimaeric bone marrow (BM) transplantation into recipient Map3k8−/− mice, lipopolysaccharide treatment did not increase circulating Ly6GhighCD11b+ cells and strongly decreased circulating Ly6GlowCD11b+ 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. Ly6GlowCD11b+ 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 Ly6GlowCD11b+ 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.
Highlights
Haematopoiesis is a tightly regulated, hierarchically organized process for maintaining appropriate numbers of immune cells
Map3k8 signalling has been studied primarily downstream of TLR4 signalling in macrophages, where it activates the Map2k1/2-Mapk1/2 pathway and participates in modulating other signal transduction pathways, such as those mediated by c-jun kinase and p70 S6 kinase[22,23,24,25]
During life-threating infections, emergency granulopoiesis is triggered to generate an effective response through the massive production of new neutrophils
Summary
Haematopoiesis is a tightly regulated, hierarchically organized process for maintaining appropriate numbers of immune cells. TLR4 activation by LPS directly triggers emergency myelopoiesis, primarily through the production of promyeloid signals predominantly involving cytokines, which instruct cells of the myeloid lineage, including HSPCs and immature granulocytes, to proliferate and differentiate into mature myeloid cells[5, 6, 8, 9]. G-CSF increases the production of CCAAT-enhancer-binding protein β Other cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α, IL-6, and interferons, are involved in emergency granulopoiesis, primarily through induction of HSPC proliferation and differentiation[3, 6, 14,15,16,17,18,19,20,21]. Map3k8 regulates LPS-induced G-CSF production, which upregulates C/EBPβ expression in immature neutrophils to trigger their amplification
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
