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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.The mobilization of myeloid progenitors initiated extramedullary myelopoiesis in the spleen in a CCR2-dependent manner resulting in augmented myelopoiesis during acute malaria.

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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Ccr2- mice induce IFN-γ-dependent chemokines but do not mobilize early myeloid progenitors.A. Serum concentration of IFN-γ induced chemokines in Ccr2- mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 4–5 mice per each experimental group. B. Phenotype of LIN− BM cells in Ccr2- mice uninfected and at day 7 after infection with P. chabaudi stained for indicated marker. C. Absolute numbers (per femur/pair) for Ccr2- LIN− c-Kithi CD27+ cells are shown as mean ± SEM per individual subsets during infection with P. chabaudi.
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ppat-1003406-g006: Ccr2- mice induce IFN-γ-dependent chemokines but do not mobilize early myeloid progenitors.A. Serum concentration of IFN-γ induced chemokines in Ccr2- mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 4–5 mice per each experimental group. B. Phenotype of LIN− BM cells in Ccr2- mice uninfected and at day 7 after infection with P. chabaudi stained for indicated marker. C. Absolute numbers (per femur/pair) for Ccr2- LIN− c-Kithi CD27+ cells are shown as mean ± SEM per individual subsets during infection with P. chabaudi.

Mentions: We therefore next investigated the consequences of CCR2 deficiency on BM hematopoiesis during acute infection with P. chabaudi. Ccr2- mice exhibited a similar upregulation of IFN-γ plasma levels within the first four days after infection compared to controls demonstrating a virtually intact IFN-γ response of CCR2 deficient hosts (Figure S6). In malaria, both CXCL10 and CCL2 serum protein levels increased reaching peak levels between day 4 and 7 after infection whereas CCL7 was constitutively deregulated in Ccr2-deficient animals (Figure 6A). The similar increase of IFN-γ levels in Ccr2- animals and controls after infection with P. chabaudi was reflected by an analogous upregulation of Sca-1 in BM Ccr2- LIN− cells and the amalgamation of HSC and HPC compartments (Figure 6B, lower panel). Despite this transformation, absence of CCR2 completely abolished the disappearance of BM myeloid progenitors, for both “CD27+ CMPs” (60.6±5.0×103 cells uninfected, 50.7±7.2×103 cells day 7 p.i.) and “GMPs” (41.8±8.4×103 cells uninfected, 59.3±6.5×103 cells day 7 p.i.), during acute malaria (Figure 6C, Table 1). In Ccr2- mice we found a clear dissociation between IFN-γ signaling in the BM as evident by the infection-induced changes in their phenotype but without any contraction in the numbers of myeloid-restricted early progenitors. Since absence of CCR2 did not affect the kinetics of the amount of serum IFN-γ and CCL2, this observation is highly suggestive for a direct engagement of CCR2 leading to the loss of myeloid progenitors.


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)

Ccr2- mice induce IFN-γ-dependent chemokines but do not mobilize early myeloid progenitors.A. Serum concentration of IFN-γ induced chemokines in Ccr2- mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 4–5 mice per each experimental group. B. Phenotype of LIN− BM cells in Ccr2- mice uninfected and at day 7 after infection with P. chabaudi stained for indicated marker. C. Absolute numbers (per femur/pair) for Ccr2- LIN− c-Kithi CD27+ cells are shown as mean ± SEM per individual subsets during infection with P. chabaudi.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675198&req=5

ppat-1003406-g006: Ccr2- mice induce IFN-γ-dependent chemokines but do not mobilize early myeloid progenitors.A. Serum concentration of IFN-γ induced chemokines in Ccr2- mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 4–5 mice per each experimental group. B. Phenotype of LIN− BM cells in Ccr2- mice uninfected and at day 7 after infection with P. chabaudi stained for indicated marker. C. Absolute numbers (per femur/pair) for Ccr2- LIN− c-Kithi CD27+ cells are shown as mean ± SEM per individual subsets during infection with P. chabaudi.
Mentions: We therefore next investigated the consequences of CCR2 deficiency on BM hematopoiesis during acute infection with P. chabaudi. Ccr2- mice exhibited a similar upregulation of IFN-γ plasma levels within the first four days after infection compared to controls demonstrating a virtually intact IFN-γ response of CCR2 deficient hosts (Figure S6). In malaria, both CXCL10 and CCL2 serum protein levels increased reaching peak levels between day 4 and 7 after infection whereas CCL7 was constitutively deregulated in Ccr2-deficient animals (Figure 6A). The similar increase of IFN-γ levels in Ccr2- animals and controls after infection with P. chabaudi was reflected by an analogous upregulation of Sca-1 in BM Ccr2- LIN− cells and the amalgamation of HSC and HPC compartments (Figure 6B, lower panel). Despite this transformation, absence of CCR2 completely abolished the disappearance of BM myeloid progenitors, for both “CD27+ CMPs” (60.6±5.0×103 cells uninfected, 50.7±7.2×103 cells day 7 p.i.) and “GMPs” (41.8±8.4×103 cells uninfected, 59.3±6.5×103 cells day 7 p.i.), during acute malaria (Figure 6C, Table 1). In Ccr2- mice we found a clear dissociation between IFN-γ signaling in the BM as evident by the infection-induced changes in their phenotype but without any contraction in the numbers of myeloid-restricted early progenitors. Since absence of CCR2 did not affect the kinetics of the amount of serum IFN-γ and CCL2, this observation is highly suggestive for a direct engagement of CCR2 leading to the loss of myeloid progenitors.

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.The mobilization of myeloid progenitors initiated extramedullary myelopoiesis in the spleen in a CCR2-dependent manner resulting in augmented myelopoiesis during acute malaria.

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