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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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Neutrophil depletion with Gr-1 mAb elicits emergency granulopoiesis                            with minimal inflammation.(A) BL/6 and congenic C3−/−,                                C1q−/−, and                                FcRγ−/− mice were treated with 100                            µg G-1 mAb; the mean numbers(+SD) of BM neutrophils (closed)                            and frequencies(+SD) of BrdU+ HSC (open) at days 1                            and 8 after treatment are shown. (B) BL/6 mice and congenic                                IL-1RI−/−, MyD88−/−,                            and RAG1−/− mice were injected with alum or 100                            µg Gr-1 mAb; the mean numbers(+SD) of BM neutrophils (closed)                            and mean frequencies(+SD) of BrdU+ HSC (open) at                            days 1 and 8 after treatment are shown. (n = 19                            BL/6 mice, day 0; n = 3–8 mice for all other                            data points). (C) BL/6 mice were treated with 100 µg Gr-1 mAb or                            100 µg Ly-6G-specific mAb (clone 1A8); the mean numbers(+SD)                            of BM neutrophils (closed diamonds for Gr-1 treatment, closed squares                            for anti-Ly-6G treatment) and frequencies(+SD) of                                BrdU+ HSC (open diamonds for Gr-1 treatment, open                            squares for anti-Ly-6G treatment) at days 1 and 8 after antibody                            injection are shown. (n = 3–5 mice for days 0                            and 1, n = 2 for both treatments at day 8).
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pone-0019957-g003: Neutrophil depletion with Gr-1 mAb elicits emergency granulopoiesis with minimal inflammation.(A) BL/6 and congenic C3−/−, C1q−/−, and FcRγ−/− mice were treated with 100 µg G-1 mAb; the mean numbers(+SD) of BM neutrophils (closed) and frequencies(+SD) of BrdU+ HSC (open) at days 1 and 8 after treatment are shown. (B) BL/6 mice and congenic IL-1RI−/−, MyD88−/−, and RAG1−/− mice were injected with alum or 100 µg Gr-1 mAb; the mean numbers(+SD) of BM neutrophils (closed) and mean frequencies(+SD) of BrdU+ HSC (open) at days 1 and 8 after treatment are shown. (n = 19 BL/6 mice, day 0; n = 3–8 mice for all other data points). (C) BL/6 mice were treated with 100 µg Gr-1 mAb or 100 µg Ly-6G-specific mAb (clone 1A8); the mean numbers(+SD) of BM neutrophils (closed diamonds for Gr-1 treatment, closed squares for anti-Ly-6G treatment) and frequencies(+SD) of BrdU+ HSC (open diamonds for Gr-1 treatment, open squares for anti-Ly-6G treatment) at days 1 and 8 after antibody injection are shown. (n = 3–5 mice for days 0 and 1, n = 2 for both treatments at day 8).

Mentions: However, mice deficient for C1q [27] or C3 [28] exhibited increased HSC proliferation and neutrophil production after Gr-1 administration that were similar to congenic BL/6 mice (Fig. 3A). In FcRγ−/− mice [29], the neutrophil depleting capacity of Gr-1 mAb was diminished, yet the lower reductions in BM neutrophil numbers remained associated with significant increases in HSC proliferation (day 1, P≤0.01) and rebounds in BM neutrophil numbers (day 8, P≤0.05) (Fig. 3A). Granulopoietic responses to Gr-1 treatment, therefore, are independent of complement or FcR-dependent events.


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

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

Neutrophil depletion with Gr-1 mAb elicits emergency granulopoiesis                            with minimal inflammation.(A) BL/6 and congenic C3−/−,                                C1q−/−, and                                FcRγ−/− mice were treated with 100                            µg G-1 mAb; the mean numbers(+SD) of BM neutrophils (closed)                            and frequencies(+SD) of BrdU+ HSC (open) at days 1                            and 8 after treatment are shown. (B) BL/6 mice and congenic                                IL-1RI−/−, MyD88−/−,                            and RAG1−/− mice were injected with alum or 100                            µg Gr-1 mAb; the mean numbers(+SD) of BM neutrophils (closed)                            and mean frequencies(+SD) of BrdU+ HSC (open) at                            days 1 and 8 after treatment are shown. (n = 19                            BL/6 mice, day 0; n = 3–8 mice for all other                            data points). (C) BL/6 mice were treated with 100 µg Gr-1 mAb or                            100 µg Ly-6G-specific mAb (clone 1A8); the mean numbers(+SD)                            of BM neutrophils (closed diamonds for Gr-1 treatment, closed squares                            for anti-Ly-6G treatment) and frequencies(+SD) of                                BrdU+ HSC (open diamonds for Gr-1 treatment, open                            squares for anti-Ly-6G treatment) at days 1 and 8 after antibody                            injection are shown. (n = 3–5 mice for days 0                            and 1, n = 2 for both treatments at day 8).
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pone-0019957-g003: Neutrophil depletion with Gr-1 mAb elicits emergency granulopoiesis with minimal inflammation.(A) BL/6 and congenic C3−/−, C1q−/−, and FcRγ−/− mice were treated with 100 µg G-1 mAb; the mean numbers(+SD) of BM neutrophils (closed) and frequencies(+SD) of BrdU+ HSC (open) at days 1 and 8 after treatment are shown. (B) BL/6 mice and congenic IL-1RI−/−, MyD88−/−, and RAG1−/− mice were injected with alum or 100 µg Gr-1 mAb; the mean numbers(+SD) of BM neutrophils (closed) and mean frequencies(+SD) of BrdU+ HSC (open) at days 1 and 8 after treatment are shown. (n = 19 BL/6 mice, day 0; n = 3–8 mice for all other data points). (C) BL/6 mice were treated with 100 µg Gr-1 mAb or 100 µg Ly-6G-specific mAb (clone 1A8); the mean numbers(+SD) of BM neutrophils (closed diamonds for Gr-1 treatment, closed squares for anti-Ly-6G treatment) and frequencies(+SD) of BrdU+ HSC (open diamonds for Gr-1 treatment, open squares for anti-Ly-6G treatment) at days 1 and 8 after antibody injection are shown. (n = 3–5 mice for days 0 and 1, n = 2 for both treatments at day 8).
Mentions: However, mice deficient for C1q [27] or C3 [28] exhibited increased HSC proliferation and neutrophil production after Gr-1 administration that were similar to congenic BL/6 mice (Fig. 3A). In FcRγ−/− mice [29], the neutrophil depleting capacity of Gr-1 mAb was diminished, yet the lower reductions in BM neutrophil numbers remained associated with significant increases in HSC proliferation (day 1, P≤0.01) and rebounds in BM neutrophil numbers (day 8, P≤0.05) (Fig. 3A). Granulopoietic responses to Gr-1 treatment, therefore, are independent of complement or FcR-dependent events.

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