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Seiichiro Sugimoto, Daniel Kreisel, Ruaihdrhi Carmody, Andrew E Gelman, Bcl3 protects against lung graft injury by limiting emergency granulopoiesis (87.7), The Journal of Immunology, Volume 182, Issue Supplement_1, April 2009, Page 87.7, https://doi.org/10.4049/jimmunol.182.Supp.87.7
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Abstract
Excessive granulocyte accumulation in solid organ grafts leads to severe tissue injury and dysfunction. However, the mechanisms that differentially regulate emergency granulopoiesis from homeostatic granulopoiesis are poorly understood. The IκB family member Bcl3 is thought to mainly control cell survival and toll-like receptor mediated inflammatory gene expression. Here we report Bcl3 expression is required to protect against lung graft injury in a mouse orthotopic lung transplantation model by attenuating emergency granulopoiesis. Notably, Bcl3 was not required for homeostatic granulopoiesis as mice reconstituted with Bcl3-/- bone marrow (B6 (Bcl3-/-)) had equivalent numbers of granulocytes as compared to control wildtype B6 (B6) mice but following lung transplantation B6 → B6 (Bcl3-/-) recipients accumulated significantly more intragraft and peripheral blood granulocytes which exacerbated graft injury relative to B6 → B6 (B6) recipients. However, graft injury and granulocyte accumulation could be significantly attenuated with G-CSF neutralizing antibodies administered to B6 (Bcl3-/-) recipients. Moreover, G-CSF but not GM-CSF or IL-3 administration to resting B6 (Bcl3-/-) mice produced 2-fold more peripheral blood granulocytes than control wildtype B6 (B6) mice. Analysis of common myeloid progenitors revealed that Bcl3 negatively regulates the proliferation and the capacity of these cells to support emergency granulopoiesis following lung transplantation as well as following G-CSF but not GM-CSF or IL-3 stimulation. These data demonstrate a critical negative regulatory role for Bcl3 in G-CSF mediated emergency granulopoiesis and suggest that modulating signals that control the differentiation of myeloid progenitors can help prevent solid organ injury.
