Abstract
Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF--serum concentrations of which rise under inflammatory conditions--rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50-dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acute Lung Injury / genetics
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Acute Lung Injury / pathology*
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Acute Lung Injury / physiopathology*
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Acute Lung Injury / prevention & control
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Animals
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B-Cell Lymphoma 3 Protein
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Base Sequence
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Cell Differentiation
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Cell Movement / physiology
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DNA Primers / genetics
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Disease Models, Animal
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Granulocyte Colony-Stimulating Factor / pharmacology
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Granulocytes / pathology
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Granulocytes / physiology*
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Humans
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Leukopoiesis / drug effects
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Leukopoiesis / genetics
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Leukopoiesis / physiology*
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Lung Transplantation / adverse effects
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Lung Transplantation / pathology
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Lung Transplantation / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Progenitor Cells / drug effects
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Myeloid Progenitor Cells / pathology
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Myeloid Progenitor Cells / physiology
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Recombinant Proteins
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Reperfusion Injury / genetics
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Reperfusion Injury / pathology
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Reperfusion Injury / physiopathology
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Reperfusion Injury / prevention & control
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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Bcl3 protein, mouse
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DNA Primers
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Proto-Oncogene Proteins
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Recombinant Proteins
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Transcription Factors
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Granulocyte Colony-Stimulating Factor