title: Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sugimoto
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tietjens
authors.forename: Jihong
authors.initials: J
authors.lastname: Zhu
authors.forename: Sumiharu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
authors.forename: Ruaidhri J
authors.initials: RJ
authors.lastname: Carmody
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D001483:Base Sequence; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000473:pathology / Q000502:physiology*; D006801:Humans; D019891:Leukopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016040:Lung Transplantation / Q000009:adverse effects / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor