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

Kreisel, D., Sugimoto, S., Tietjens, J., Zhu, J., Yamamoto, S., Krupnick, A.S., Carmody, R.J. and Gelman, A.E. (2011) Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. Journal of Clinical Investigation, 121(1), pp. 265-276. (doi: 10.1172/JCI42596)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carmody, Dr Ruaidhri
• Authors: Kreisel, D., Sugimoto, S., Tietjens, J., Zhu, J., Yamamoto, S., Krupnick, A.S., Carmody, R.J., and Gelman, A.E.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Clinical Investigation
• Journal Abbr.: JCI
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Published Online: 13 December 2010
• Copyright Holders: Copyright © 2011 Americal Society for Clinical Investigation
• First Published: First published in Journal of Clinical Investigation 121(1):265-276
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher