Abstract
Emergency monocytopoiesis is an inflammation-driven hematological process that supplies the periphery with monocytes and subsequently with macrophages and monocyte-derived dendritic cells. Yet, the regulatory mechanisms by which early bone marrow myeloid progenitors commit to monocyte-derived phagocytes during endotoxemia remains elusive. Herein, we show that type I interferons signaling promotes the differentiation of monocyte-derived phagocytes at the level of their progenitors during a mouse model of endotoxemia. In this model, we characterized early changes in the numbers of conventional dendritic cells, monocyte-derived antigen-presenting cells and their respective precursors. While loss of caspase-1/11 failed to impair a shift toward monocytopoiesis, we observed sustained type-I-IFN-dependent monocyte progenitors differentiation in the bone marrow correlated to an accumulation of Mo-APCs in the spleen. Importantly, IFN-alpha and -beta were found to efficiently generate the development of monocyte-derived antigen-presenting cells while having no impact on the precursor activity of conventional dendritic cells. Consistently, the LPS-driven decrease of conventional dendritic cells and their direct precursor occurred independently of type-I-IFN signaling in vivo. Our characterization of early changes in mononuclear phagocytes and their dependency on type I IFN signaling during sepsis opens the way to the development of treatments for limiting the immunosuppressive state associated with sepsis.
Highlights
Sepsis is a relatively common, life-threatening syndrome in which a systemic bacterial infection triggers a dysregulated host inflammatory response and leading to an immunosuppressive state associated with the development of secondary and nosocomial infections[1,2,3]
We found that (i) conventional dendritic cells (cDCs) and their precursors were impaired by a low-dose LPS injection, and (ii) LPS-induced induction of monocyte-derived antigen-presenting cells (Mo-APCs) and their precursors was dependent on type I IFN signaling in spleen and bone marrow
We showed for the first time that type I IFN, IFNα and IFNβ, modulate the fate of macrophage and DC progenitor (MDP)/common monocyte progenitor (cMoP) and increase monocytic progeny
Summary
Sepsis is a relatively common, life-threatening syndrome in which a systemic bacterial infection triggers a dysregulated host inflammatory response and leading to an immunosuppressive state associated with the development of secondary and nosocomial infections[1,2,3]. As most deaths in human sepsis occur during the prolonged period of immunosuppression that follows the acute inflammation, we used a murine model of non-lethal endotoxemia to determine the role of type I IFNs in emergency monocytopoiesis and in the decrease of conventional dendritic cells (cDCs). There are several subsets of DCs, which originate from either monocytic precursors differentiating into monocyte-derived antigen-presenting cells (Mo-APCs) or from non-monocytic progenitors differentiating into cDCs28,29 Both lineages are generally studied by characterizing their surface markers; all the subsets display the integrin CD11c and major histocompatibility complex class II (MHCII). We demonstrated that IFNα/β allows the generation of Mo-APCs from MDPs in vitro, without impairing cDC development This knowledge of the upstream modulation of medullar monocytopoiesis and their dependency on type I IFN signaling is likely to facilitate the development of treatments that limit the immunosuppressive state associated with sepsis
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