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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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IL-1RI-dependent induction of G-CSF is critical for BM neutrophil                            mobilization and increased HSPC proliferation after alum                            immunization.(A) Serum G-CSF concentrations in BL/6 (closed) and                                IL-1RI−/− (open) mice after alum                            immunization. The mean(+SD) of serum G-CSF concentration is shown;                            statistical differences between G-CSF concentrations in BL/6 and                                IL-1RI−/− mice at each interval are indicated                            (n = 3–7). (B) Effects of G-CSF                            neutralization on alum-induced HSC and GMP proliferation. BL/6 mice were                            treated or not with anti-G-CSF mAb, then immunized or not with alum;                            mice were sacrificed 24 hours later for analysis. Six hours prior to                            sacrifice, mice were injected i.p. with BrdU; the mean                            frequencies(+SD) of BrdU+ cells in the HSC and GMP                            compartments are shown (n = 4–5). (C) Alum                            immunization of G-CSF-R−/− mice. BL/6 and                                G-CSF-R−/− mice were immunized with alum                            (grey) or left untreated (open), and then analyzed for BrdU uptake in                            HSC and GMP compartments 24 hours later                            (n = 3–9). (D) Effects of G-CSF                            neutralization on BM neutrophil mobilization after alum immunization. BM                            neutrophils were enumerated 24 hours after immunization (Fig.                                S1 defines neutrophil populations). The mean                            numbers(+SD) of mature neutrophils in the leg bones are shown for                            each treatment (n = 4–5). (E) BL/6 or                                G-CSF-R−/− mice were immunized with alum                            (grey) or left untreated (open), and the number of BM neutrophils was                            determined 24 hours later (n = 3–9). *,                            P≤0.05; **, P≤0.01; n.s., not significant.
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pone-0019957-g001: IL-1RI-dependent induction of G-CSF is critical for BM neutrophil mobilization and increased HSPC proliferation after alum immunization.(A) Serum G-CSF concentrations in BL/6 (closed) and IL-1RI−/− (open) mice after alum immunization. The mean(+SD) of serum G-CSF concentration is shown; statistical differences between G-CSF concentrations in BL/6 and IL-1RI−/− mice at each interval are indicated (n = 3–7). (B) Effects of G-CSF neutralization on alum-induced HSC and GMP proliferation. BL/6 mice were treated or not with anti-G-CSF mAb, then immunized or not with alum; mice were sacrificed 24 hours later for analysis. Six hours prior to sacrifice, mice were injected i.p. with BrdU; the mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments are shown (n = 4–5). (C) Alum immunization of G-CSF-R−/− mice. BL/6 and G-CSF-R−/− mice were immunized with alum (grey) or left untreated (open), and then analyzed for BrdU uptake in HSC and GMP compartments 24 hours later (n = 3–9). (D) Effects of G-CSF neutralization on BM neutrophil mobilization after alum immunization. BM neutrophils were enumerated 24 hours after immunization (Fig. S1 defines neutrophil populations). The mean numbers(+SD) of mature neutrophils in the leg bones are shown for each treatment (n = 4–5). (E) BL/6 or G-CSF-R−/− mice were immunized with alum (grey) or left untreated (open), and the number of BM neutrophils was determined 24 hours later (n = 3–9). *, P≤0.05; **, P≤0.01; n.s., not significant.

Mentions: Alum elicits reactive neutrophilia by increasing HSC and GMP proliferation through an IL-1RI-dependent pathway [3]. Since G-CSF is an important regulator of granulopoiesis [14], we determined if alum induces G-CSF via IL-1RI by measuring G-CSF concentrations in the serum of immunized BL/6 and congenic IL-1RI−/− mice. In BL/6 mice, G-CSF concentrations rose from 70 pg/ml to 2.5 ng/ml at 6 h after immunization, and remained elevated at 0.7 ng/ml for two days after injection (Fig. 1A). Although serum G-CSF concentrations were equivalent in naïve BL/6 and IL-1RI−/− mice, G-CSF production in response to alum in IL-1RI−/− mice was significantly impaired (Fig. 1A), indicating that alum induces G-CSF via IL-1RI-dependent signals.


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

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

IL-1RI-dependent induction of G-CSF is critical for BM neutrophil                            mobilization and increased HSPC proliferation after alum                            immunization.(A) Serum G-CSF concentrations in BL/6 (closed) and                                IL-1RI−/− (open) mice after alum                            immunization. The mean(+SD) of serum G-CSF concentration is shown;                            statistical differences between G-CSF concentrations in BL/6 and                                IL-1RI−/− mice at each interval are indicated                            (n = 3–7). (B) Effects of G-CSF                            neutralization on alum-induced HSC and GMP proliferation. BL/6 mice were                            treated or not with anti-G-CSF mAb, then immunized or not with alum;                            mice were sacrificed 24 hours later for analysis. Six hours prior to                            sacrifice, mice were injected i.p. with BrdU; the mean                            frequencies(+SD) of BrdU+ cells in the HSC and GMP                            compartments are shown (n = 4–5). (C) Alum                            immunization of G-CSF-R−/− mice. BL/6 and                                G-CSF-R−/− mice were immunized with alum                            (grey) or left untreated (open), and then analyzed for BrdU uptake in                            HSC and GMP compartments 24 hours later                            (n = 3–9). (D) Effects of G-CSF                            neutralization on BM neutrophil mobilization after alum immunization. BM                            neutrophils were enumerated 24 hours after immunization (Fig.                                S1 defines neutrophil populations). The mean                            numbers(+SD) of mature neutrophils in the leg bones are shown for                            each treatment (n = 4–5). (E) BL/6 or                                G-CSF-R−/− mice were immunized with alum                            (grey) or left untreated (open), and the number of BM neutrophils was                            determined 24 hours later (n = 3–9). *,                            P≤0.05; **, P≤0.01; n.s., not significant.
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pone-0019957-g001: IL-1RI-dependent induction of G-CSF is critical for BM neutrophil mobilization and increased HSPC proliferation after alum immunization.(A) Serum G-CSF concentrations in BL/6 (closed) and IL-1RI−/− (open) mice after alum immunization. The mean(+SD) of serum G-CSF concentration is shown; statistical differences between G-CSF concentrations in BL/6 and IL-1RI−/− mice at each interval are indicated (n = 3–7). (B) Effects of G-CSF neutralization on alum-induced HSC and GMP proliferation. BL/6 mice were treated or not with anti-G-CSF mAb, then immunized or not with alum; mice were sacrificed 24 hours later for analysis. Six hours prior to sacrifice, mice were injected i.p. with BrdU; the mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments are shown (n = 4–5). (C) Alum immunization of G-CSF-R−/− mice. BL/6 and G-CSF-R−/− mice were immunized with alum (grey) or left untreated (open), and then analyzed for BrdU uptake in HSC and GMP compartments 24 hours later (n = 3–9). (D) Effects of G-CSF neutralization on BM neutrophil mobilization after alum immunization. BM neutrophils were enumerated 24 hours after immunization (Fig. S1 defines neutrophil populations). The mean numbers(+SD) of mature neutrophils in the leg bones are shown for each treatment (n = 4–5). (E) BL/6 or G-CSF-R−/− mice were immunized with alum (grey) or left untreated (open), and the number of BM neutrophils was determined 24 hours later (n = 3–9). *, P≤0.05; **, P≤0.01; n.s., not significant.
Mentions: Alum elicits reactive neutrophilia by increasing HSC and GMP proliferation through an IL-1RI-dependent pathway [3]. Since G-CSF is an important regulator of granulopoiesis [14], we determined if alum induces G-CSF via IL-1RI by measuring G-CSF concentrations in the serum of immunized BL/6 and congenic IL-1RI−/− mice. In BL/6 mice, G-CSF concentrations rose from 70 pg/ml to 2.5 ng/ml at 6 h after immunization, and remained elevated at 0.7 ng/ml for two days after injection (Fig. 1A). Although serum G-CSF concentrations were equivalent in naïve BL/6 and IL-1RI−/− mice, G-CSF production in response to alum in IL-1RI−/− mice was significantly impaired (Fig. 1A), indicating that alum induces G-CSF via IL-1RI-dependent signals.

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