High MafB expression following burn augments monocyte commitment and inhibits DC differentiation in hemopoietic progenitors.

Abstract

We have previously shown that perturbed bone marrow progenitor development promotes hyporesponsive monocytes following experimental burn sepsis. Clinical and experimental sepsis is associated with monocyte deactivation and depletion of mDCs. Decrease in circulating DCs is reported in burn patients who develop sepsis. In our 15% TBSA scald burn model, we demonstrate a significant reduction in the circulating MHC-II(+) population and mDCs (Gr1(neg)CD11b(+)CD11c(+)) with a corresponding decrease in bone marrow MHC-II(+) cells and mDCs for up to 14 days following burn. We explored the underlying mechanism(s) that regulate bone marrow development of monocytes and DCs following burn injury. We found a robust bone marrow response with a significant increase in multipotential HSCs (LSK) and bipotential GMPs following burn injury. GMPs from burn mice exhibit a significant reduction in GATA-1, which is essential for DC development, but express high levels of MafB and M-CSFRs, both associated with monocyte production. GMPs obtained from burn mice differentiated 1.7 times more into Mϕ and 1.6-fold less into DCs compared with sham. Monocytes and DCs expressed 50% less MHC-II in burn versus sham. Increased monocyte commitment in burn GMPs was a result of high MafB and M-CSFR expressions. Transient silencing of MafB (siRNA) in GMP-derived monocytes from burn mice partially restored DC differentiation deficits and increased GATA-1 expression. We provide evidence that high MafB following burn plays an inhibitory role in monocyte-derived DC differentiation by regulating M-CSFR and GATA-1 expressions.

• Authors: Kirstin Howell, Joseph Posluszny, Li K He, Andrea Szilagyi, John Halerz, Richard L Gamelli, Ravi Shankar, Kuzhali Muthu
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 91 Issue 1 Pg. 69-81 (Jan 2012) ISSN: 1938-3673 [Electronic] United States
• PMID: 21984745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GATA1 Transcription Factor
• Gata1 protein, mouse
• Growth Inhibitors
• MafB Transcription Factor
• Mafb protein, mouse
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Animals
• Burns (immunology, metabolism, pathology)
• Cell Differentiation (immunology)
• Dendritic Cells (cytology, immunology)
• Disease Models, Animal
• Down-Regulation (immunology)
• GATA1 Transcription Factor (genetics, physiology)
• Growth Inhibitors (biosynthesis, genetics, physiology)
• Hematopoietic Stem Cells (cytology, immunology)
• MafB Transcription Factor (biosynthesis, genetics, physiology)
• Male
• Mice
• Mice, Inbred Strains
• Monocytes (cytology, immunology, metabolism)
• Receptor, Macrophage Colony-Stimulating Factor (genetics, physiology)
• Sepsis (immunology, metabolism, pathology)
• Up-Regulation (immunology)