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
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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

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Figure 1

Granulocytes promote lung graft injury in Bcl3-deficient recipients.

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Granulocytes promote lung graft injury in Bcl3-deficient recipients. (A)...
(A) Assessment of PaO2 (left) and exclusion of EBD (right) 6 and 24 hours following B6 → B6 (B6) or B6 → B6 (Bcl3–/–) lung engraftment. (B and C) Representative graft histology (original magnification, ×100) (n = 11) (B) and intragraft MPO activity (C) 24 hours following B6 → B6 (B6) or B6 → B6 (Bcl3–/–) lung engraftment. (D) Left: Representative FACS analysis (n = 5). Numbers denote percent abundance of granulocytes in graft tissue. Right: Granulocyte counts in BAL at 6 and 24 hours following B6 → B6 (B6) or B6 → B6 (Bcl3–/–) lung engraftment. (E) Left: B6 → B6 (Bcl3–/–) lung recipients were partially depleted for granulocytes with Ly6G-specific antibodies or treated with control Ig 4 hours prior to transplantation and assessed for percent abundance of granulocytes in graft tissue 24 hours after engraftment. Right: Granulocyte counts at 6 and 24 hours following engraftment in BAL. (F) Assessment of PaO2 (left) and EBD exclusion (right) at 6 and 24 hours following engraftment. (G) Representative lung graft histology (original magnification, ×100) of B6 → B6 (Bcl3–/–) recipients 24 hours after engraftment following treatment with either control Ig or Ly6G-specific antibodies (n = 4). Data are mean ± SD and, unless otherwise indicated, represent at least 3 independent experiments. *P < 0.05; **P < 0.01.