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Cited by 95Hematopoietic Stem Cell TransplantationBlood disorders and treatmentsPlatelet Disorders and Treatments

Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism

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Cain, Derek W., Snowden, Pilar B., Sempowski, Gregory D., Kelsoe, Garnett·2011·PLoS ONE
DOI 10.1371/journal.pone.0019957PMC PMC3104996
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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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  • Published BM chimera studies show that in vivo HSC proliferation in response to IL-1 can be triggered independently of IL-1 receptor (IL-1R) on HSCs themselves and may rely on IL-1R-induced G-CSF production in the BM niche.

    “published BM chimera studies show that in vivo HSC proliferation in response to IL-1 can be triggered independently of IL-1 receptor (IL-1R) on HSCs themselves (Cain et al., 2011; Ueda et al., 2009) and may rely on IL-1R–induced G-CSF production in the BM niche.”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Cain et al., 2011

    The Results section (‘Emergency granulopoiesis in the absence of inflammation’; page unavailable) states that IL-1RI expression by radiation-resistant cells is necessary for alum-induced emergency granulopoiesis, supporting the idea that IL-1RI need not be on HSCs themselves. The Results section (‘Alum induces HSPC proliferation via IL-1RI-dependent G-CSF induction’; page unavailable) also shows IL-1RI-dependent G-CSF induction and a requirement for G-CSF in the HSC response. However, this paper cites earlier work for the radiation-resistant-cell finding; it does not itself report BM chimera studies or establish G-CSF production specifically in the BM niche. (LLM, conf=0.85)

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Authors
Cain, D. W., Snowden, P. B., Sempowski, G. D., & Kelsoe, G.
Affiliations
Duke University (US)
Corresponding author
Kelsoe, Garnett
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-05-31
Volume
6
Issue
5
Pages
e19957
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0019957
PMC
PMC3104996
OpenAlex
W2032923651
Cited by
95
References
50
Citations by year
2026: 5 · 2025: 6 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 6 · 2013: 9 · 2012: 4
FWCI
4.39
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (AI 56363)
  • National Institute of Allergy and Infectious Diseases (R01AI024335, AI 24335, UC6AI058607, P30AI051445, U19AI056363, AI-56363)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
emergency granulopoiesis, inflammation, C/EBPβ, C/EBPα, granulocyte colony-stimulating factor, G-CSF receptor, alum adjuvant, hematopoietic stem and progenitor cells, bone marrow neutrophils, neutropenia, Mcl-1, granulocytic differentiation, density-dependent feedback, neutrophilia
MeSH terms
Alum Compounds, Animals, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Granulocytes, Hematopoietic Stem Cells, Inflammation, Mice, Inbred C57BL, Neutropenia, Granulocyte Colony-Stimulating Factor, Leukopoiesis, Mice

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