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Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism.

Cain DW, Snowden PB, Sempowski GD, Kelsoe G - PLoS ONE (2011)

Bottom Line: Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF.The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant.We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.

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Adjuvant inflammation and experimental neutropenia elicit similar                            changes in granulopoiesis.BL/6 mice were i.p. injected with Gr-1 mAb [10 µg (open                            squares), 100 µg (closed diamonds)] or alum (shaded                            triangles), and then blood and BM neutrophils were enumerated at various                            intervals. Neutrophils numbers were also determined in Mcl-1-                            mice and control littermates. The mean(+SD) numbers of                            neutrophils/ml of blood (A) and in the four leg bones (B) after each                            treatment are shown. In the right panel, the numbers of blood and BM                            neutrophils in Mcl-1+ and Mcl-1− mice                            are indicated. Proliferation of HSC (C), MPP (D), and GMP (E) at                            intervals after alum or Gr-1 treatment, and in Mcl-1+                            and Mcl-1− mice, was determined by BrdU incorporation.                            Mice were injected with BrdU 6 hours prior to sacrifice, and the mean                            frequency(+SD) of BrdU+ cells in each compartment                            is shown (day 0, n = 19; for other intervals,                            n = 3–10). (F) BM neutrophil numbers (closed                            diamonds) and frequencies of BrdU+ HSC (open squares)                            after injection of Gr-1 or alum (as shown in B and C) are co-plotted;                            the values at each interval represent the fold change from naïve                            mice, expressed as log2. Pearson product moment correlation                            coefficients (R) between BM neutrophil numbers and the frequencies of                                BrdU+ HSC for each treatment are shown. (G) BL/6                            mice were injected with graded amounts of Gr-1 mAb (0, 0.1, 1, 10, and                            100 µg; n = 4–7 mice per treatment) and                            then BM neutrophil numbers and HSC proliferation were determined two                            days later. Significant differences from naïve BL/6 mice are shown                            for neutrophil numbers (**, P≤0.01) and frequency of                                BrdU+ HSC (††, P≤0.01);                            the Pearson product moment correlation coefficient (R) for BM neutrophil                            numbers and frequencies of BrdU+ HSC is shown.
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pone-0019957-g002: Adjuvant inflammation and experimental neutropenia elicit similar changes in granulopoiesis.BL/6 mice were i.p. injected with Gr-1 mAb [10 µg (open squares), 100 µg (closed diamonds)] or alum (shaded triangles), and then blood and BM neutrophils were enumerated at various intervals. Neutrophils numbers were also determined in Mcl-1- mice and control littermates. The mean(+SD) numbers of neutrophils/ml of blood (A) and in the four leg bones (B) after each treatment are shown. In the right panel, the numbers of blood and BM neutrophils in Mcl-1+ and Mcl-1− mice are indicated. Proliferation of HSC (C), MPP (D), and GMP (E) at intervals after alum or Gr-1 treatment, and in Mcl-1+ and Mcl-1− mice, was determined by BrdU incorporation. Mice were injected with BrdU 6 hours prior to sacrifice, and the mean frequency(+SD) of BrdU+ cells in each compartment is shown (day 0, n = 19; for other intervals, n = 3–10). (F) BM neutrophil numbers (closed diamonds) and frequencies of BrdU+ HSC (open squares) after injection of Gr-1 or alum (as shown in B and C) are co-plotted; the values at each interval represent the fold change from naïve mice, expressed as log2. Pearson product moment correlation coefficients (R) between BM neutrophil numbers and the frequencies of BrdU+ HSC for each treatment are shown. (G) BL/6 mice were injected with graded amounts of Gr-1 mAb (0, 0.1, 1, 10, and 100 µg; n = 4–7 mice per treatment) and then BM neutrophil numbers and HSC proliferation were determined two days later. Significant differences from naïve BL/6 mice are shown for neutrophil numbers (**, P≤0.01) and frequency of BrdU+ HSC (††, P≤0.01); the Pearson product moment correlation coefficient (R) for BM neutrophil numbers and frequencies of BrdU+ HSC is shown.

Mentions: The Gr-1 mAb is used routinely in vivo to deplete neutrophils [37], [38]. We injected BL/6 mice i.p. with 10- or 100 µg of Gr-1 mAb and compared the loss and recovery of mature neutrophils in blood and BM to that induced by alum [3]. Whereas alum elicited a multiphasic neutrophilia in blood, both doses of Gr-1 induced transient neutropenias (>90% reductions; P≤0.01) for 2 to 4 days (10- or 100 µg Gr-1, respectively) with recovery on days 6 or 8 (10- or 100 µg Gr-1, respectively) (Fig. 2A). The effects of Gr-1 mAb were specific, as injection of 100 µg rat IgG had no effect on blood or BM leukocyte numbers (unpublished data).


Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism.

Cain DW, Snowden PB, Sempowski GD, Kelsoe G - PLoS ONE (2011)

Adjuvant inflammation and experimental neutropenia elicit similar                            changes in granulopoiesis.BL/6 mice were i.p. injected with Gr-1 mAb [10 µg (open                            squares), 100 µg (closed diamonds)] or alum (shaded                            triangles), and then blood and BM neutrophils were enumerated at various                            intervals. Neutrophils numbers were also determined in Mcl-1-                            mice and control littermates. The mean(+SD) numbers of                            neutrophils/ml of blood (A) and in the four leg bones (B) after each                            treatment are shown. In the right panel, the numbers of blood and BM                            neutrophils in Mcl-1+ and Mcl-1− mice                            are indicated. Proliferation of HSC (C), MPP (D), and GMP (E) at                            intervals after alum or Gr-1 treatment, and in Mcl-1+                            and Mcl-1− mice, was determined by BrdU incorporation.                            Mice were injected with BrdU 6 hours prior to sacrifice, and the mean                            frequency(+SD) of BrdU+ cells in each compartment                            is shown (day 0, n = 19; for other intervals,                            n = 3–10). (F) BM neutrophil numbers (closed                            diamonds) and frequencies of BrdU+ HSC (open squares)                            after injection of Gr-1 or alum (as shown in B and C) are co-plotted;                            the values at each interval represent the fold change from naïve                            mice, expressed as log2. Pearson product moment correlation                            coefficients (R) between BM neutrophil numbers and the frequencies of                                BrdU+ HSC for each treatment are shown. (G) BL/6                            mice were injected with graded amounts of Gr-1 mAb (0, 0.1, 1, 10, and                            100 µg; n = 4–7 mice per treatment) and                            then BM neutrophil numbers and HSC proliferation were determined two                            days later. Significant differences from naïve BL/6 mice are shown                            for neutrophil numbers (**, P≤0.01) and frequency of                                BrdU+ HSC (††, P≤0.01);                            the Pearson product moment correlation coefficient (R) for BM neutrophil                            numbers and frequencies of BrdU+ HSC is shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3104996&req=5

pone-0019957-g002: Adjuvant inflammation and experimental neutropenia elicit similar changes in granulopoiesis.BL/6 mice were i.p. injected with Gr-1 mAb [10 µg (open squares), 100 µg (closed diamonds)] or alum (shaded triangles), and then blood and BM neutrophils were enumerated at various intervals. Neutrophils numbers were also determined in Mcl-1- mice and control littermates. The mean(+SD) numbers of neutrophils/ml of blood (A) and in the four leg bones (B) after each treatment are shown. In the right panel, the numbers of blood and BM neutrophils in Mcl-1+ and Mcl-1− mice are indicated. Proliferation of HSC (C), MPP (D), and GMP (E) at intervals after alum or Gr-1 treatment, and in Mcl-1+ and Mcl-1− mice, was determined by BrdU incorporation. Mice were injected with BrdU 6 hours prior to sacrifice, and the mean frequency(+SD) of BrdU+ cells in each compartment is shown (day 0, n = 19; for other intervals, n = 3–10). (F) BM neutrophil numbers (closed diamonds) and frequencies of BrdU+ HSC (open squares) after injection of Gr-1 or alum (as shown in B and C) are co-plotted; the values at each interval represent the fold change from naïve mice, expressed as log2. Pearson product moment correlation coefficients (R) between BM neutrophil numbers and the frequencies of BrdU+ HSC for each treatment are shown. (G) BL/6 mice were injected with graded amounts of Gr-1 mAb (0, 0.1, 1, 10, and 100 µg; n = 4–7 mice per treatment) and then BM neutrophil numbers and HSC proliferation were determined two days later. Significant differences from naïve BL/6 mice are shown for neutrophil numbers (**, P≤0.01) and frequency of BrdU+ HSC (††, P≤0.01); the Pearson product moment correlation coefficient (R) for BM neutrophil numbers and frequencies of BrdU+ HSC is shown.
Mentions: The Gr-1 mAb is used routinely in vivo to deplete neutrophils [37], [38]. We injected BL/6 mice i.p. with 10- or 100 µg of Gr-1 mAb and compared the loss and recovery of mature neutrophils in blood and BM to that induced by alum [3]. Whereas alum elicited a multiphasic neutrophilia in blood, both doses of Gr-1 induced transient neutropenias (>90% reductions; P≤0.01) for 2 to 4 days (10- or 100 µg Gr-1, respectively) with recovery on days 6 or 8 (10- or 100 µg Gr-1, respectively) (Fig. 2A). The effects of Gr-1 mAb were specific, as injection of 100 µg rat IgG had no effect on blood or BM leukocyte numbers (unpublished data).

Bottom Line: Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF.The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant.We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.

Show MeSH
Related in: MedlinePlus