Journal Article

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

Gelman, Andrew E., Tietjens, Jeremy, Zhu, Jihong, Kreisel, Daniel, Yamamoto, Sumiharu, Sugimoto, Seiichiro, Krupnick, Alexander S., Carmody, Ruaidhri J.

2011

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Abnormalities / Acute Lung Injury - genetics / Acute Lung Injury - pathology / Acute Lung Injury - physiopathology / Acute Lung Injury - prevention & control / Animals / Base Sequence / Biomedical research / Bone marrow / Cell Differentiation / Cell Movement - physiology / Cytokines / Disease Models, Animal / DNA Primers - genetics / Granulocyte Colony-Stimulating Factor - pharmacology / Granulocytes / Granulocytes - pathology / Granulocytes - physiology / Histology / Humans / Ischemia / Leukemia / Leukopoiesis - drug effects / Leukopoiesis - genetics / Leukopoiesis - physiology / Lung diseases / Lung Transplantation - adverse effects / Lung Transplantation - pathology / Lung Transplantation - physiology / Lymphoma / Mice / Mice, Inbred C57BL / Mice, Knockout / Myeloid Progenitor Cells - drug effects / Myeloid Progenitor Cells - pathology / Myeloid Progenitor Cells - physiology / Physiological aspects / Prevention / Proto-Oncogene Proteins - deficiency / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - physiology / Recombinant Proteins / Reperfusion Injury - genetics / Reperfusion Injury - pathology / Reperfusion Injury - physiopathology / Reperfusion Injury - prevention & control / Risk factors / Transcription factors / Transcription Factors - deficiency / Transcription Factors - genetics / Transcription Factors - physiology / Transplants & implants