Limits...
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.

Show MeSH

Related in: MedlinePlus

Neutrophil depletion elicits G-CSF-dependent and -independent HSPC                            proliferation.(A) Serum from naïve BL/6, Mcl-1+ (closed circle),                                Mcl-1− (open circle) mice, and BL/6 mice treated                            with alum (open triangles) or Gr-1 mAb (closed diamonds) was analyzed                            for G-CSF in a multiplex bead array. The mean concentrations(+SD)                            of G-CSF/ml of serum are shown (n = 3–7). (B)                            Serum G-CSF in BL/6 (closed) and IL-1RI−/− (open)                            mice after Gr-1 administration; the mean concentrations(+SD) of                            G-CSF/ml are shown (n = 3–5). (C) Effect of                            G-CSF neutralization on proliferative response of HSPC to induced                            neutropenia. BL/6 mice were injected or not with anti-GCSF, then                            administered Gr-1 mAb. The mean frequencies(+SD) of                                BrdU+ cells in the HSC and GMP compartments, and the                            numbers(+SD) of BM neutrophils on day 1 after treatment are shown                            (n = 4–5). (D) BL/6 and                                G-CSF-R−/− mice were treated or not with Gr-1                            mAb, then sacrificed 24 hours later for analysis. The mean                            frequencies(+SD) of BrdU+ cells in the HSC and GMP                            compartments, and the mean numbers(+SD) of BM neutrophils are shown                            (n = 3–9). *, P≤0.05; **,                            P≤0.01.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3104996&req=5

pone-0019957-g004: Neutrophil depletion elicits G-CSF-dependent and -independent HSPC proliferation.(A) Serum from naïve BL/6, Mcl-1+ (closed circle), Mcl-1− (open circle) mice, and BL/6 mice treated with alum (open triangles) or Gr-1 mAb (closed diamonds) was analyzed for G-CSF in a multiplex bead array. The mean concentrations(+SD) of G-CSF/ml of serum are shown (n = 3–7). (B) Serum G-CSF in BL/6 (closed) and IL-1RI−/− (open) mice after Gr-1 administration; the mean concentrations(+SD) of G-CSF/ml are shown (n = 3–5). (C) Effect of G-CSF neutralization on proliferative response of HSPC to induced neutropenia. BL/6 mice were injected or not with anti-GCSF, then administered Gr-1 mAb. The mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments, and the numbers(+SD) of BM neutrophils on day 1 after treatment are shown (n = 4–5). (D) BL/6 and G-CSF-R−/− mice were treated or not with Gr-1 mAb, then sacrificed 24 hours later for analysis. The mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments, and the mean numbers(+SD) of BM neutrophils are shown (n = 3–9). *, P≤0.05; **, P≤0.01.

Mentions: Alum increased serum IL-5, IL-6, KC, MCP-1 (Fig. S4), and G-CSF (Fig. 4A); the serum levels of these cytokines peaked at 6 h after injection and then returned to normal (Fig. S4). Gr-1 administration elicited only KC, MCP-1 (Fig. S4), and G-CSF (Fig. 4A). In contrast to the rapid rise in serum G-CSF elicited by alum, there was no increase in G-CSF 6 h after Gr-1 injection (Fig. 4A) but G-CSF levels gradually increased to those observed in alum-treated mice on days 1 and 2 before returning to control levels on day 8 (Fig. 4A). In neutropenic Mcl-1− mice, G-CSF (Fig. 4A) and KC (Fig. S4) were also constitutively elevated compared to control littermates.


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

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

Neutrophil depletion elicits G-CSF-dependent and -independent HSPC                            proliferation.(A) Serum from naïve BL/6, Mcl-1+ (closed circle),                                Mcl-1− (open circle) mice, and BL/6 mice treated                            with alum (open triangles) or Gr-1 mAb (closed diamonds) was analyzed                            for G-CSF in a multiplex bead array. The mean concentrations(+SD)                            of G-CSF/ml of serum are shown (n = 3–7). (B)                            Serum G-CSF in BL/6 (closed) and IL-1RI−/− (open)                            mice after Gr-1 administration; the mean concentrations(+SD) of                            G-CSF/ml are shown (n = 3–5). (C) Effect of                            G-CSF neutralization on proliferative response of HSPC to induced                            neutropenia. BL/6 mice were injected or not with anti-GCSF, then                            administered Gr-1 mAb. The mean frequencies(+SD) of                                BrdU+ cells in the HSC and GMP compartments, and the                            numbers(+SD) of BM neutrophils on day 1 after treatment are shown                            (n = 4–5). (D) BL/6 and                                G-CSF-R−/− mice were treated or not with Gr-1                            mAb, then sacrificed 24 hours later for analysis. The mean                            frequencies(+SD) of BrdU+ cells in the HSC and GMP                            compartments, and the mean numbers(+SD) of BM neutrophils are shown                            (n = 3–9). *, P≤0.05; **,                            P≤0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104996&req=5

pone-0019957-g004: Neutrophil depletion elicits G-CSF-dependent and -independent HSPC proliferation.(A) Serum from naïve BL/6, Mcl-1+ (closed circle), Mcl-1− (open circle) mice, and BL/6 mice treated with alum (open triangles) or Gr-1 mAb (closed diamonds) was analyzed for G-CSF in a multiplex bead array. The mean concentrations(+SD) of G-CSF/ml of serum are shown (n = 3–7). (B) Serum G-CSF in BL/6 (closed) and IL-1RI−/− (open) mice after Gr-1 administration; the mean concentrations(+SD) of G-CSF/ml are shown (n = 3–5). (C) Effect of G-CSF neutralization on proliferative response of HSPC to induced neutropenia. BL/6 mice were injected or not with anti-GCSF, then administered Gr-1 mAb. The mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments, and the numbers(+SD) of BM neutrophils on day 1 after treatment are shown (n = 4–5). (D) BL/6 and G-CSF-R−/− mice were treated or not with Gr-1 mAb, then sacrificed 24 hours later for analysis. The mean frequencies(+SD) of BrdU+ cells in the HSC and GMP compartments, and the mean numbers(+SD) of BM neutrophils are shown (n = 3–9). *, P≤0.05; **, P≤0.01.
Mentions: Alum increased serum IL-5, IL-6, KC, MCP-1 (Fig. S4), and G-CSF (Fig. 4A); the serum levels of these cytokines peaked at 6 h after injection and then returned to normal (Fig. S4). Gr-1 administration elicited only KC, MCP-1 (Fig. S4), and G-CSF (Fig. 4A). In contrast to the rapid rise in serum G-CSF elicited by alum, there was no increase in G-CSF 6 h after Gr-1 injection (Fig. 4A) but G-CSF levels gradually increased to those observed in alum-treated mice on days 1 and 2 before returning to control levels on day 8 (Fig. 4A). In neutropenic Mcl-1− mice, G-CSF (Fig. 4A) and KC (Fig. S4) were also constitutively elevated compared to control littermates.

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