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.

RORC1 Regulates Tumor-Promoting “Emergency” Granulo-Monocytopoiesis

“…Our study indicates that RORC1 impinges on cancer-driven myelopoiesis by suppressing negative (Socs3 and Bcl3) (Croker et al, 2004;Kreisel et al, 2011) and promoting positive (C/EBPb) (Hirai et al, 2006) transcriptional regulators of ''emergency'' granulopoiesis, while instating the expression of macrophage-specific transcription factors IRF8 and PU.1 (Friedman, 2007). Depletion of RORC1 + F4/80 + CD115 + TAMs with anti-CSFR1 antibody enhanced the recruitment of mature (CD16/CD32 high ) RORC1 À inflammatory neutrophils, with diminished expansion of immature RORC1 + (CD16 low /CD32 low ) PMN-MDSCs.…”

“…We observed a mild but significant decrease of mRNA expression of PU.1, C/EBPb, and C/EBPa in spleens and BM from Rorc1 À/À >WT tumor bearers, paralleled by decreased C/EBPb protein levels in splenic PMN-MDSCs and M-MDSCs ( Figure 6A). Importantly, BM and spleens from Rorc1 À/À >WT MN/MCA1 tumor bearers displayed increased mRNA levels of the suppressor of cytokine signaling-3 (Socs3) and the transcriptional co-regulator B cell leukemia/lymphoma 3 (Bcl3) ( Figure 6B), both potent inhibitors of G-CSF-driven granulopoiesis (Croker et al, 2004;Kreisel et al, 2011). In agreement with the IFN-g-mediated inhibition of G-CSF-driven neutrophilia (Ulich et al, 1988), IFN-g induced a strong increase of Socs3 and Bcl3 mRNA in splenic PMN-MDSCs from Rorc1 À/À tumor bearers ( Figure 6B, right).…”

NF-κB, the first quarter-century: remarkable progress and outstanding questions

“…Induction of BCL-3 in T cells during infection or immunization promotes the survival of activated T cells Valenzuela et al 2005;Bauer et al 2006). BCL-3 also exhibits anti-inflammatory function by limiting granulopoiesis under settings of acute inflammation (Kreisel et al 2011). It remains to be determined whether the effects of BCL-3 on granulopoiesis-or, for that matter, similar effects on T-cell differentiation and survival (Rangelova et al 2008)-are due to repression of p50-or p52-dependent transcriptional responses.…”

Mapping the Interaction of B Cell Leukemia 3 (BCL-3) and Nuclear Factor κB (NF-κB) p50 Identifies a BCL-3-mimetic Anti-inflammatory Peptide

“…BCL-3 is important for establishing TLR tolerance, a state of altered responsiveness to Toll-like receptor stimulation in macrophage characterized by a block in proinflammatory cytokine expression (8). Mice deficient in Bcl3 lack Toll-like receptor tolerance (8), fail to clear infection (9), are more sensitive to the development of type I diabetes (10), and undergo increased granulopoiesis under inflammatory conditions (11). More recently BCL-3 has been identified as an important enforcer of T cell differentiation states (12) and a key factor in promoting dendritic cell priming of T cells (13).…”