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Extramedullary myelopoiesis in malaria depends on mobilization of myeloid-restricted progenitors by IFN-γ induced chemokines.

Belyaev NN, Biró J, Langhorne J, Potocnik AJ - PLoS Pathog. (2013)

Bottom Line: De-activation of IFN-γ signaling completely abrogated the contraction of BM 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, London, United Kingdom.

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- 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.

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Contraction of lineage negative cell and Sca-1 upregulation in malaria are dependent on IFN-γ signaling.A. Reduction of LIN− and c-Kit (CD117) positive cells in the BM during infection of C57BL/6 mice with P. chabaudi. Significant contraction of absolute numbers was recorded at day 4 and day 7 after infection for LIN− cells and at day 7 for c-Kit+ cells. Ifngr1- mice did not undergo any significant loss of LIN− or c-Kit+ BM cells during acute malaria. Data represent mean ± SEM of cell number per femur/pair obtained from 15 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with 4–5 mice per group (*:P≤0.05; **: P≤0.01, Mann-Whitney U-test). B. LIN− BM cells from uninfected controls and malaria-infected animals at day 7 of infection with P. chabaudi were co-stained with c-Kit and Sca-1. Of note is the lack of Sca-1 upregulation on Ifngr1­ cells during acute malaria. Data are representative for 19 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with numbers in individual plots indicating the frequency (in %) of the respective population.
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ppat-1003406-g001: Contraction of lineage negative cell and Sca-1 upregulation in malaria are dependent on IFN-γ signaling.A. Reduction of LIN− and c-Kit (CD117) positive cells in the BM during infection of C57BL/6 mice with P. chabaudi. Significant contraction of absolute numbers was recorded at day 4 and day 7 after infection for LIN− cells and at day 7 for c-Kit+ cells. Ifngr1- mice did not undergo any significant loss of LIN− or c-Kit+ BM cells during acute malaria. Data represent mean ± SEM of cell number per femur/pair obtained from 15 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with 4–5 mice per group (*:P≤0.05; **: P≤0.01, Mann-Whitney U-test). B. LIN− BM cells from uninfected controls and malaria-infected animals at day 7 of infection with P. chabaudi were co-stained with c-Kit and Sca-1. Of note is the lack of Sca-1 upregulation on Ifngr1­ cells during acute malaria. Data are representative for 19 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with numbers in individual plots indicating the frequency (in %) of the respective population.

Mentions: Infection of C57BL/6 mice with the malaria parasite P. chabaudi results in an acute systemic infection characterized by peak parasitemia at day 7 of infection (Figure S1) and subsequent severe anemia. Parallel to the acute infection the absolute number of LIN− BM cells, mainly consisting of hematopoietic progenitors and precursors, were significantly decreased in infected wild type mice resulting in the lowest number of LIN− cells at peak parasitemia (Figure 1A). Similarly we observed a significant reduction in the number of c-Kit+ (CD117) BM cells. This infection-induced process was accompanied by changes in the phenotype of these LIN− cells. HSCs and multipotent progenitors are characterized in steady state by high expression of c-Kit and Sca-1 [16]. In contrast, HPCs are negative for Sca-1 but still retain high levels of c-Kit at the surface. The HPC subset constitutes the most abundant cell pool within the LIN− pool in the BM. At day 7 of infection with P. chabaudi the LIN− compartment showed an upregulation of Sca-1 expression on virtually all c-Kithi cells (Figure 1B). Since Sca-1 is induced by pro-inflammatory cytokines [17], namely IFN-γ, we investigated the cellularity and phenotype of the LIN− compartment during acute malaria in the absence of IFN-γ signaling. Mice deficient for IFN-γ receptor did not show a significant change in the numbers of LIN− or c-Kit+ cells in the BM (Figure 1A). In addition, expression of c-Kit and Sca-1 remained unchanged on LIN− cells of Ifngr1- mice at day 7 of infection indicating the dependence of Sca-1 induction on intact IFN-γ signaling (Figure 1B).


Extramedullary myelopoiesis in malaria depends on mobilization of myeloid-restricted progenitors by IFN-γ induced chemokines.

Belyaev NN, Biró J, Langhorne J, Potocnik AJ - PLoS Pathog. (2013)

Contraction of lineage negative cell and Sca-1 upregulation in malaria are dependent on IFN-γ signaling.A. Reduction of LIN− and c-Kit (CD117) positive cells in the BM during infection of C57BL/6 mice with P. chabaudi. Significant contraction of absolute numbers was recorded at day 4 and day 7 after infection for LIN− cells and at day 7 for c-Kit+ cells. Ifngr1- mice did not undergo any significant loss of LIN− or c-Kit+ BM cells during acute malaria. Data represent mean ± SEM of cell number per femur/pair obtained from 15 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with 4–5 mice per group (*:P≤0.05; **: P≤0.01, Mann-Whitney U-test). B. LIN− BM cells from uninfected controls and malaria-infected animals at day 7 of infection with P. chabaudi were co-stained with c-Kit and Sca-1. Of note is the lack of Sca-1 upregulation on Ifngr1­ cells during acute malaria. Data are representative for 19 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with numbers in individual plots indicating the frequency (in %) of the respective population.
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Related In: Results  -  Collection

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ppat-1003406-g001: Contraction of lineage negative cell and Sca-1 upregulation in malaria are dependent on IFN-γ signaling.A. Reduction of LIN− and c-Kit (CD117) positive cells in the BM during infection of C57BL/6 mice with P. chabaudi. Significant contraction of absolute numbers was recorded at day 4 and day 7 after infection for LIN− cells and at day 7 for c-Kit+ cells. Ifngr1- mice did not undergo any significant loss of LIN− or c-Kit+ BM cells during acute malaria. Data represent mean ± SEM of cell number per femur/pair obtained from 15 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with 4–5 mice per group (*:P≤0.05; **: P≤0.01, Mann-Whitney U-test). B. LIN− BM cells from uninfected controls and malaria-infected animals at day 7 of infection with P. chabaudi were co-stained with c-Kit and Sca-1. Of note is the lack of Sca-1 upregulation on Ifngr1­ cells during acute malaria. Data are representative for 19 infection experiments (C57BL/6) or four experiments (Ifngr1- mice) each with numbers in individual plots indicating the frequency (in %) of the respective population.
Mentions: Infection of C57BL/6 mice with the malaria parasite P. chabaudi results in an acute systemic infection characterized by peak parasitemia at day 7 of infection (Figure S1) and subsequent severe anemia. Parallel to the acute infection the absolute number of LIN− BM cells, mainly consisting of hematopoietic progenitors and precursors, were significantly decreased in infected wild type mice resulting in the lowest number of LIN− cells at peak parasitemia (Figure 1A). Similarly we observed a significant reduction in the number of c-Kit+ (CD117) BM cells. This infection-induced process was accompanied by changes in the phenotype of these LIN− cells. HSCs and multipotent progenitors are characterized in steady state by high expression of c-Kit and Sca-1 [16]. In contrast, HPCs are negative for Sca-1 but still retain high levels of c-Kit at the surface. The HPC subset constitutes the most abundant cell pool within the LIN− pool in the BM. At day 7 of infection with P. chabaudi the LIN− compartment showed an upregulation of Sca-1 expression on virtually all c-Kithi cells (Figure 1B). Since Sca-1 is induced by pro-inflammatory cytokines [17], namely IFN-γ, we investigated the cellularity and phenotype of the LIN− compartment during acute malaria in the absence of IFN-γ signaling. Mice deficient for IFN-γ receptor did not show a significant change in the numbers of LIN− or c-Kit+ cells in the BM (Figure 1A). In addition, expression of c-Kit and Sca-1 remained unchanged on LIN− cells of Ifngr1- mice at day 7 of infection indicating the dependence of Sca-1 induction on intact IFN-γ signaling (Figure 1B).

Bottom Line: De-activation of IFN-γ signaling completely abrogated the contraction of BM 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, London, United Kingdom.

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- 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.

Show MeSH
Related in: MedlinePlus