Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism.
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.
Type
Journal articleSubject
Alum CompoundsAnimals
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Granulocyte Colony-Stimulating Factor
Granulocytes
Hematopoietic Stem Cells
Inflammation
Leukopoiesis
Mice
Mice, Inbred C57BL
Neutropenia
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https://hdl.handle.net/10161/10903Published Version (Please cite this version)
10.1371/journal.pone.0019957Publication Info
Cain, Derek W; Snowden, Pilar B; Sempowski, Gregory D; & Kelsoe, Garnett (2011). Inflammation triggers emergency granulopoiesis through a density-dependent feedback
mechanism. PLoS One, 6(5). pp. e19957. 10.1371/journal.pone.0019957. Retrieved from https://hdl.handle.net/10161/10903.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Derek Wilson Cain
Associate Professor in Medicine
My research focuses on the interactions of T cells and B cells during infection or
following vaccination. I am particularly interested in the inter- and intracellular
events that take place within germinal centers, the anatomic site of antibody evolution
during an immune response.
Garnett H. Kelsoe
James B. Duke Distinguished Professor of Immunology
1. Lymphocyte development and antigen-driven diversification of immunoglobulin and
T cell antigen receptor genes. 2. The germinal center reaction and mechanisms for
clonal selection and self - tolerance. The origins of autoimmunity. 3. Interaction
of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses,
Gregory David Sempowski
Professor in Medicine
Dr. Sempowski earned his PhD in Immunology from the University of Rochester and was
specifically trained in the areas of inflammation, wound healing, and host response
(innate and adaptive). Dr. Sempowski contributed substantially to the field of lung
inflammation and fibrosis defining the roles of pulmonary fibroblast heterogeneity
and CD40/CD40L signaling in regulating normal and pathogenic lung inflammation. During
his postdoctoral training with Dr. Barton F. H
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