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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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Changes in chemokines and chemokine receptor expression during acute malaria.A. Serum concentration of IFN-γ induced chemokines in C57BL/6 and Ifngr1-deficient mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 5–6 mice per each experimental group. B. Cell surface expression of CD192 (CCR2) on myelo-erythroid progenitors in the BM of mice infected with P. chabaudi day 7 (lower part) or before infection. All data are representative of two independent experiments with 4–5 mice per group each. Black line represents signals in Ccr2−/− animals for comparison.
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ppat-1003406-g005: Changes in chemokines and chemokine receptor expression during acute malaria.A. Serum concentration of IFN-γ induced chemokines in C57BL/6 and Ifngr1-deficient mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 5–6 mice per each experimental group. B. Cell surface expression of CD192 (CCR2) on myelo-erythroid progenitors in the BM of mice infected with P. chabaudi day 7 (lower part) or before infection. All data are representative of two independent experiments with 4–5 mice per group each. Black line represents signals in Ccr2−/− animals for comparison.

Mentions: To dissect further the molecular mechanism resulting in a depletion of early stages of BM myeloid progenitors we analyzed the pattern of IFN-γ-induced cytokines and chemokines during acute infection with P. chabaudi in wild-type and Ifngr1- mice. After infection of wild-type mice with P. chabaudi the Stat1-dependent chemokines CXCL10 (IP-10), CCL2 (MCP-1) and CCL7 (MCP-3) reached relative serum peak levels by day 7 after infection with the notable exception of CCL2 which was the most abundant in the circulation already at day 4 (Figure 5A). The upregulation of these chemokines was critically dependent on IFN-γ signaling as demonstrated by their virtual absence in Ifngr1- animals during acute malaria. Furthermore the increase in levels of CXCL10 and CCL7 occurred subsequently to the infection-induced upregulation of IFN-γ, since peak levels for this cytokine were reached in C57BL/6 mice 2–3 days earlier (Figure S6). Remarkably the levels of serum CCL2 followed closely the respective kinetics for IFN-γ in C57BL/6 wild type mice. Myd88/Trif- mice exhibited a pattern of secretion of IFN-γ (Figure S6) as well as IFN-γ induced chemokines mostly identical to C57BL/6 controls with a peak of CCL2 at day 4 of infection (Figure S7). The common receptor for CCL2 and CCL7, C-C chemokine receptor type 2 (CCR2; CD192), was measured on the surface of BM HPCs by flow cytometry. In uninfected mice both CD27+ CMP and GMPs stained dimly positive for CCR2 whereas CD27− CMPs and MEPs were negative (Figure 5B, upper panel). After infection with P. chabaudi the strongly reduced compartment of BM “CD27+ CMPs” and “GMPs” lacked detectable surface levels of CCR2 (Figure 5B, lower panel) suggesting that residual myeloid progenitors were unable to egress from the BM via this chemokine-signaling pathway. Based on these observations we hypothesized that stroma-derived CCL2/CCL7 by binding to CCR2 could be the main stimuli for the mobilization of myeloid progenitors from the BM explaining their strongly reduced presence in this compartment.


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)

Changes in chemokines and chemokine receptor expression during acute malaria.A. Serum concentration of IFN-γ induced chemokines in C57BL/6 and Ifngr1-deficient mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 5–6 mice per each experimental group. B. Cell surface expression of CD192 (CCR2) on myelo-erythroid progenitors in the BM of mice infected with P. chabaudi day 7 (lower part) or before infection. All data are representative of two independent experiments with 4–5 mice per group each. Black line represents signals in Ccr2−/− animals for comparison.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675198&req=5

ppat-1003406-g005: Changes in chemokines and chemokine receptor expression during acute malaria.A. Serum concentration of IFN-γ induced chemokines in C57BL/6 and Ifngr1-deficient mice infected with P. chabaudi. Data are shown as mean ± SEM of serum concentration of respective chemokine in three infection experiments with 5–6 mice per each experimental group. B. Cell surface expression of CD192 (CCR2) on myelo-erythroid progenitors in the BM of mice infected with P. chabaudi day 7 (lower part) or before infection. All data are representative of two independent experiments with 4–5 mice per group each. Black line represents signals in Ccr2−/− animals for comparison.
Mentions: To dissect further the molecular mechanism resulting in a depletion of early stages of BM myeloid progenitors we analyzed the pattern of IFN-γ-induced cytokines and chemokines during acute infection with P. chabaudi in wild-type and Ifngr1- mice. After infection of wild-type mice with P. chabaudi the Stat1-dependent chemokines CXCL10 (IP-10), CCL2 (MCP-1) and CCL7 (MCP-3) reached relative serum peak levels by day 7 after infection with the notable exception of CCL2 which was the most abundant in the circulation already at day 4 (Figure 5A). The upregulation of these chemokines was critically dependent on IFN-γ signaling as demonstrated by their virtual absence in Ifngr1- animals during acute malaria. Furthermore the increase in levels of CXCL10 and CCL7 occurred subsequently to the infection-induced upregulation of IFN-γ, since peak levels for this cytokine were reached in C57BL/6 mice 2–3 days earlier (Figure S6). Remarkably the levels of serum CCL2 followed closely the respective kinetics for IFN-γ in C57BL/6 wild type mice. Myd88/Trif- mice exhibited a pattern of secretion of IFN-γ (Figure S6) as well as IFN-γ induced chemokines mostly identical to C57BL/6 controls with a peak of CCL2 at day 4 of infection (Figure S7). The common receptor for CCL2 and CCL7, C-C chemokine receptor type 2 (CCR2; CD192), was measured on the surface of BM HPCs by flow cytometry. In uninfected mice both CD27+ CMP and GMPs stained dimly positive for CCR2 whereas CD27− CMPs and MEPs were negative (Figure 5B, upper panel). After infection with P. chabaudi the strongly reduced compartment of BM “CD27+ CMPs” and “GMPs” lacked detectable surface levels of CCR2 (Figure 5B, lower panel) suggesting that residual myeloid progenitors were unable to egress from the BM via this chemokine-signaling pathway. Based on these observations we hypothesized that stroma-derived CCL2/CCL7 by binding to CCR2 could be the main stimuli for the mobilization of myeloid progenitors from the BM explaining their strongly reduced presence in this compartment.

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