Extramedullary Myelopoiesis in Malaria Depends on Mobilization of Myeloid-Restricted Progenitors by IFN-γ Induced Chemokines

N.N. Belyaev, J. Biró, J. Langhorne, A.J. Potocnik

Research output: Contribution to journalArticlepeer-review

Abstract

Resolution of a variety of acute bacterial and parasitic infections critically relies on the stimulation of myelopoiesis leading in cases to extramedullary hematopoiesis. Here, we report the isolation of the earliest myeloid-restricted progenitors in acute infection with the rodent malaria parasite, Plasmodium chabaudi. The rapid disappearance of these infection-induced myeloid progenitors from the bone marrow (BM) equated with contraction of the functional myeloid potential in that organ. The loss of BM myelopoiesis was not affected by the complete genetic inactivation of toll-like receptor signaling. De-activation of IFN-γ signaling completely abrogated the contraction of BM myeloid progenitors. Radiation chimeras of Ifngr1-null and control BM revealed that IFN-γ signaling in an irradiation-resistant stromal compartment was crucial for the loss of early myeloid progenitors. Systemic IFN-γ triggered the secretion of C-C motif ligand chemokines CCL2 and CCL7 leading to the egress of early, myeloid-committed progenitors from the bone marrow mediated by their common receptor CCR2. The mobilization of myeloid progenitors initiated extramedullary myelopoiesis in the spleen in a CCR2-dependent manner resulting in augmented myelopoiesis during acute malaria. Consistent with the lack of splenic myelopoiesis in the absence of CCR2 we observed a significant persistence of parasitemia in malaria infected CCR2-deficient hosts. Our findings reveal how the activated immune system mobilizes early myeloid progenitors out of the BM thereby transiently establishing myelopoiesis in the spleen in order to contain and resolve the infection locally.
Original languageEnglish
Article numbere1003406
JournalPLoS Pathogens
Volume9
Issue number6
DOIs
Publication statusPublished - 6 Jun 2013

Keywords

  • CD27 antigen
  • chemokine
  • chemokine receptor CCR2
  • gamma interferon
  • monocyte chemotactic protein 1
  • monocyte chemotactic protein 3
  • toll like receptor
  • animal model
  • article
  • bone marrow cell
  • cell differentiation
  • erythroid cell
  • flow cytometry
  • fluorescence activated cell sorting
  • hematopoiesis
  • immune system
  • malaria
  • megakaryocyte erythroid progenitor
  • mouse
  • myeloid progenitor cell
  • myelopoiesis
  • nonhuman
  • parasitemia
  • Plasmodium chabaudi
  • real time polymerase chain reaction
  • Animals
  • Chemokine CCL2
  • Chemokine CCL7
  • Hematopoiesis, Extramedullary
  • Interferon-gamma
  • Malaria
  • Mice
  • Mice, Knockout
  • Myeloid Progenitor Cells
  • Myelopoiesis
  • Receptors, CCR2
  • Signal Transduction
  • Spleen
  • Toll-Like Receptors
  • Bacteria (microorganisms)
  • Rodentia

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