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

C/EBPβ is dispensable for proliferative responses of HSPC to Gr-1                            administration or alum immunization.C/EBPβ−/− mice (open) and control littermates                            (closed) were injected with 10 µg Gr-1 mAb (A) or alum (B). The                            mean numbers(+SD) of mature and immature neutrophils (Fig.                                S1) in BM, and mean frequencies(+SD) of                                BrdU+ cells in the HSC, MPP, and GMP compartments at                            different intervals after treatment are shown. Significant differences                            between C/EBPβ+ and                                C/EBPβ−/− mice at corresponding intervals                            are indicated (day 0, n = 12 for                                C/EBPβ+ mice and n = 7 for                                C/EBPβ−/− mice; for all others,                            n = 3–5 mice). **, P≤0.01.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3104996&req=5

pone-0019957-g005: C/EBPβ is dispensable for proliferative responses of HSPC to Gr-1 administration or alum immunization.C/EBPβ−/− mice (open) and control littermates (closed) were injected with 10 µg Gr-1 mAb (A) or alum (B). The mean numbers(+SD) of mature and immature neutrophils (Fig. S1) in BM, and mean frequencies(+SD) of BrdU+ cells in the HSC, MPP, and GMP compartments at different intervals after treatment are shown. Significant differences between C/EBPβ+ and C/EBPβ−/− mice at corresponding intervals are indicated (day 0, n = 12 for C/EBPβ+ mice and n = 7 for C/EBPβ−/− mice; for all others, n = 3–5 mice). **, P≤0.01.

Mentions: C/EBPβ−/− mice had equivalent numbers of BM neutrophils as C/EBPβ+ mice (Fig. 5A), consistent with previous reports [45], and neutrophils were similarly depleted by Gr-1 mAb (Fig. 5A). However, the supranormal recovery of BM neutrophils was blunted in mice lacking C/EBPβ (Fig. 5A); BM neutrophil numbers peaked on day 6 only modestly higher than in untreated mice (1.7-fold, P≤0.05), and were only half of that in C/EBPβ+ mice at the same interval (P≤0.01) (Fig. 5A). Thus, C/EBPβ is required for optimal granulopoietic responses to neutropenia.


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

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

C/EBPβ is dispensable for proliferative responses of HSPC to Gr-1                            administration or alum immunization.C/EBPβ−/− mice (open) and control littermates                            (closed) were injected with 10 µg Gr-1 mAb (A) or alum (B). The                            mean numbers(+SD) of mature and immature neutrophils (Fig.                                S1) in BM, and mean frequencies(+SD) of                                BrdU+ cells in the HSC, MPP, and GMP compartments at                            different intervals after treatment are shown. Significant differences                            between C/EBPβ+ and                                C/EBPβ−/− mice at corresponding intervals                            are indicated (day 0, n = 12 for                                C/EBPβ+ mice and n = 7 for                                C/EBPβ−/− mice; for all others,                            n = 3–5 mice). **, P≤0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019957-g005: C/EBPβ is dispensable for proliferative responses of HSPC to Gr-1 administration or alum immunization.C/EBPβ−/− mice (open) and control littermates (closed) were injected with 10 µg Gr-1 mAb (A) or alum (B). The mean numbers(+SD) of mature and immature neutrophils (Fig. S1) in BM, and mean frequencies(+SD) of BrdU+ cells in the HSC, MPP, and GMP compartments at different intervals after treatment are shown. Significant differences between C/EBPβ+ and C/EBPβ−/− mice at corresponding intervals are indicated (day 0, n = 12 for C/EBPβ+ mice and n = 7 for C/EBPβ−/− mice; for all others, n = 3–5 mice). **, P≤0.01.
Mentions: C/EBPβ−/− mice had equivalent numbers of BM neutrophils as C/EBPβ+ mice (Fig. 5A), consistent with previous reports [45], and neutrophils were similarly depleted by Gr-1 mAb (Fig. 5A). However, the supranormal recovery of BM neutrophils was blunted in mice lacking C/EBPβ (Fig. 5A); BM neutrophil numbers peaked on day 6 only modestly higher than in untreated mice (1.7-fold, P≤0.05), and were only half of that in C/EBPβ+ mice at the same interval (P≤0.01) (Fig. 5A). Thus, C/EBPβ is required for optimal granulopoietic responses to neutropenia.

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