Type I interferons drive inflammasome-independent emergency monocytopoiesis during endotoxemia

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.

Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection

“…Next, we assessed the role of other pro-inflammatory cytokines including type I IFNs, TNF-α, and IL-6, all of which are known to trigger emergency myelopoiesis, in altered DC differentiation [ 34 , 37 , 39 , 44 – 46 ]. The abrogation of type I IFN signalling did not influence the numbers of CDPs and pre-DCs in the BM ( Fig 6D ).…”

“…We hypothesized that the pro-inflammatory cytokine storm following IAV infection is responsible for altering DC development in the BM. It has been reported that type I IFNs, IL-6 and TNF-α promote emergency monopoiesis in some settings [ 39 , 60 , 61 ]. Here, we found that the decrease in the number of CDPs and pre-DCs during IAV infection is independent of these cytokines.…”

“…g . type I and II interferons (IFN)) produced systemically [ 29 , 30 , 32 , 34 , 37 , 39 ] or locally in the BM [ 33 ].…”

Understanding the Cellular Origin of the Mononuclear Phagocyte System Sheds Light on the Myeloid Postulate of Immune Paralysis in Sepsis

“…Lipopolysaccharides (LPS) of the Gram negative bacilli Yersinia enterocolitica are sensed by radio-resistant cells that produce IFNγ, inducing a selective differentiation of myeloid progenitors toward the monocytic lineage (monocytopoiesis) at the expense of conventional DC (cDC) ( 17 ). Moreover, R848 and LPS induce the production of type I IFN involved in the differentiation of myeloid progenitors toward the monocytic lineage ( 18 , 19 ). cDC, conventional dendritic cell; CDP, common dendritic cell progenitor; Pre-DC, precursor of cDCs; pDC, plasmacytoide DC; cMoP, common monocyte progenitor; Mo-DC, monocyte-derived dendritic cells, Mo-Mac, monocyte-derived macrophages; IFNγ, interferon γ; TLR toll-like receptor.…”

“…Some of these cytokines are induced by these danger signals, such as type I IFN. Indeed, type I IFN gives rise to Mo-APCs by acting through the IFNAR receptor on direct monocyte progenitors (Figure 1 ) ( 18 ). Similar to DAMPs, microbiota-dependent metabolites affect the balance between Mo-DCs and macrophages.…”