Innate immune stimuli modulate bone marrow-derived dendritic cell production in vitro by toll-like receptor-dependent and -independent mechanisms

Abstract

Haematopoiesis is crucial for immunity because it results in the production of leucocytes. Bacterial and viral infections alter leucocyte production by promoting granulopoiesis or lymphopoiesis. Recent studies suggest that changes in leucocyte production may be caused by the effects of inflammatory responses on the differentiation of haematopoietic progenitors in the bone marrow. We investigated the mechanisms through which infection regulates the formation of bone marrow-derived dendritic cells (BMDCs) in vitro. We mimicked infection by stimulating developing cells with molecules associated with bacteria and viruses and with inactivated influenza viruses. We showed that toll-like receptor (TLR) ligands act as modulators of haematopoiesis, and that signalling through different TLRs results in differing effects on the production of BMDCs. We demonstrated that ligands for TLR3 and influenza viruses reduce the production of BMDCs, resulting in increased neutrophil numbers, and that ligands for TLR4 and TLR9 drive the production of plasmacytoid dendritic cells. Furthermore, there are distinct signalling mechanisms involved in these effects. Signalling pathways triggered by TLR4 and TLR9 involve MyD88 and are partially mediated by the cytokine tumour necrosis factor-α (TNF-α). Mechanisms activated by TLR3 were Tir-domain-containing adaptor-inducing interferon dependent. Haematopoietic modulation induced by inactivated influenza viruses was associated with the activation of an antiviral pathway mediated by type-1 interferons.