Innate immune system favors emergency monopoiesis at the expense of DC‐differentiation to control systemic bacterial infection in mice

Abstract

DCs are professional APCs playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of bone marrow (BM) hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4-and IFN-γ−signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive

Type I interferons drive inflammasome-independent emergency monocytopoiesis during endotoxemia

“…To determine the effects of LPS on cMoPs, bone marrow cells were counted in WT mice after an injection of LPS or PBS. As reported previously in the context of bacterial infection 45 , a significant drop in the number of cMoP precursor cells was observed 24 h after LPS injection (Fig. 3A and B ).…”

“…To determine whether this decrease in cMoPs resulted from accelerated differentiation into monoblasts and promonocyte (pro-Mo) cells (as suggested by 45 ), we counted these precursors in the bone marrow. Monoblasts were defined as live singlet Lin − CD115 + CD11c − MHCII − Ly6C + Sca-1 + CD11b − cells, and pro-Mo cells were defined as live singlet Lin − CD115 + CD11c − MHCII − Ly6C + Sca-1 + CD11b + cells 45 . We detected a significant increase in the number of monoblasts and pro-Mo cells within the bone marrow after LPS injection when compared to PBS injection (Fig.…”

“…As positive and negative effects of type-I IFN on HSPCs are described in the literature 37 , we measured the proliferation and number of LSK bone marrow cells (Lin − Sca-1 + c-kit + ) 45 , 46 . LSK cells were gated as described in Supplementary Figure S4A 45 , and a significant increase of their number and proliferation, evaluated by BrdU incorporation, was observed in a type-I IFN independent manner (see Supplementary Figure S4B ). Then, LPS induced the generation of monocyte precursors 24 h after its injection in a type-I dependent manner.…”

New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection

“…In immunocompromised patients, systemic infection can lead to focal abscesses in the spleen and liver [ 9 ]. Similar clinical manifestations have been found in a murine model of systemic Yersinia infection, with Ye also being detectable in the lymph nodes, bone marrow and lungs at one day post-infection [ 10 - 11 ]. The virulence of Ye is associated with Yersinia adhesin A (YadA), a trimeric autotransporter that mediates cell adhesion.…”

Cannabinoid Receptor 2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia

“…During sepsis, emergency myelopoiesis is triggered in the bone marrow in response to signals from G-CSF released in the blood by the injured endothelium [ 41 , 58 , 59 ]. Hematopoietic stem cells proliferate giving rise to neutrophils that egress from the bone marrow and enter the circulation [ 41 , 60 ].…”