Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis
Daniel Kreisel, Seiichiro Sugimoto, Jeremy Tietjens, Jihong Zhu, Sumiharu Yamamoto, Alexander S. Krupnick, Ruaidhri J. Carmody, Andrew E. Gelman
Daniel Kreisel, Seiichiro Sugimoto, Jeremy Tietjens, Jihong Zhu, Sumiharu Yamamoto, Alexander S. Krupnick, Ruaidhri J. Carmody, Andrew E. Gelman
View: Text | PDF
Research Article Inflammation

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

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

×

Figure 4

Proliferation and differentiation of Bcl3-deficient myeloid progenitors.

Options: View larger image (or click on image) Download as PowerPoint
Proliferation and differentiation of Bcl3-deficient myeloid progenitors....
(A) Left: Methylcellulose colony count from B6 or Bcl3–/– bone marrow cells cultured with indicated cytokines. Right: Number of cells per colony. Data are representative of 2 independent experiments. (B) Representative FACS analysis (n = 4) of MPO expression in liquid CMP cultures following 18 hours of stimulation with indicated cytokines. Numbers within histograms indicate percent abundance of MPO+ cells. (C) Granulocyte output from CMP liquid cultures following 72 hours of stimulation with indicated cytokines. (D) Indicated transcript accumulation in peripheral blood granulocytes isolated from B6 (B6) or B6 (Bcl3–/–) mice 24 hours following a 5-μg injection of G-CSF. (E) Indicated transcript accumulation in CMPs isolated from B6 (B6) or B6 (Bcl3–/–) mice 24 hours following injection of 5 μg of indicated cytokines. (F) Bottom: CMP BrdU incorporation in response to indicated concentrations of G-CSF, GM-CSF, or IL-3 following 18 hours of liquid culture. Data are representative of at least 3 independent experiments. Top: Cyclin D3 transcript accumulation in CMPs isolated from B6 (B6) or B6 (Bcl3–/–) mice 24 hours following injection of 5 μg of indicated cytokines. (G) Representative (n = 3) BrdU incorporation of bone marrow Lin–Sca-1–c-Kit+ cells (GMPs; CD34+CD16/32+) and (CMPs; CD34+CD16/32–) in B6 →B6 (B6) or B6 (Bcl3–/–) lung recipients 24 hours following transplantation. Dot plot numbers indicate percent abundance. Data represent mean ± SD. *P < 0.05; **P < 0.01.