Department of Surgery, Mount Sinai Medical Center, Chicago, Illinois, USA.
J Leukoc Biol. 2012 Jan;91(1):69-81. doi: 10.1189/jlb.0711338. Epub 2011 Oct 7.
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.
我们之前已经表明，骨髓祖细胞发育失调会促进实验性烧伤脓毒症后反应迟钝的单核细胞。临床和实验性败血症与单核细胞失活和 mDC 耗竭有关。据报道，发生败血症的烧伤患者循环 DC 减少。在我们的 15%TBSA 烫伤烧伤模型中，我们发现在烧伤后长达 14 天内，循环 MHC-II(+)群体和 mDC（Gr1(neg)CD11b(+)CD11c(+)）显著减少，骨髓 MHC-II(+)细胞和 mDC 也相应减少。我们探讨了调节烧伤后骨髓单核细胞和 DC 发育的潜在机制。我们发现，烧伤后骨髓出现强烈反应，多潜能 HSCs（LSK）和双潜能 GMP 显著增加。来自烧伤小鼠的 GMP 表现出 GATA-1 的显著减少，GATA-1 对 DC 发育至关重要，但表达高水平的 MafB 和 M-CSFRs，两者都与单核细胞产生有关。与 sham 相比，来自烧伤小鼠的 GMP 分化为 Mϕ 的比例增加了 1.7 倍，分化为 DC 的比例减少了 1.6 倍。与 sham 相比，烧伤小鼠的单核细胞和 DC 表达的 MHC-II 减少了 50%。烧伤 GMP 中单核细胞的高分化是由于 MafB 和 M-CSFR 表达增加所致。用小干扰 RNA（siRNA）瞬时沉默烧伤小鼠 GMP 衍生单核细胞中的 MafB 部分恢复了 DC 分化缺陷，并增加了 GATA-1 表达。我们提供的证据表明，烧伤后高 MafB 通过调节 M-CSFR 和 GATA-1 表达，对单核细胞衍生的 DC 分化发挥抑制作用。
