Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, D-45147 Essen, Germany.
J Immunol. 2011 Jan 15;186(2):977-86. doi: 10.4049/jimmunol.1001147. Epub 2010 Dec 15.
Murine polymicrobial sepsis is associated with a sustained reduction of dendritic cell (DC) numbers in lymphoid organs and with a dysfunction of DC that is considered to mediate the chronic susceptibility of post-septic mice to secondary infections. We investigated whether polymicrobial sepsis triggered an altered de novo formation and/or differentiation of DC in the bone marrow. BrdU labeling experiments indicated that polymicrobial sepsis did not affect the formation of splenic DC. DC that differentiated from bone marrow (bone marrow-derived DC [BMDC]) of post-septic mice released enhanced levels of IL-10 but did not show an altered phenotype in comparison with BMDC from sham mice. Adoptive transfer experiments of BMDC into naive mice revealed that BMDC from post-septic mice impaired Th1 priming but not Th cell expansion and suppressed the innate immune defense mechanisms against Pseudomonas bacteria in the lung. Accordingly, BMDC from post-septic mice inhibited the release of IFN-γ from NK cells that are critical for the protection against Pseudomonas. Additionally, sepsis was associated with a loss of resident DC in the bone marrow. Depletion of resident DC from bone marrow of sham mice led to the differentiation of BMDC that were impaired in Th1 priming similar to BMDC from post-septic mice. Thus, in response to polymicrobial sepsis, DC precursor cells in the bone marrow developed into regulatory DC that impaired Th1 priming and NK cell activity and mediated immunosuppression. The absence of resident DC in the bone marrow after sepsis might have contributed to the modulation of DC differentiation.
鼠多微生物脓毒症与淋巴器官中树突状细胞 (DC) 数量的持续减少以及 DC 功能障碍有关，后者被认为介导了脓毒症后小鼠对二次感染的慢性易感性。我们研究了多微生物脓毒症是否引发骨髓中 DC 的新形成和/或分化改变。BrdU 标记实验表明，多微生物脓毒症不会影响脾 DC 的形成。与 sham 小鼠的 BMDC 相比，从脓毒症小鼠分化而来的 DC 释放出增强水平的 IL-10，但表型没有改变。将 BMDC 过继转移到未感染的小鼠中表明，来自脓毒症小鼠的 BMDC 损害了 Th1 启动，但不影响 Th 细胞扩增，并抑制了肺中针对铜绿假单胞菌的固有免疫防御机制。因此，来自脓毒症小鼠的 BMDC 抑制了对铜绿假单胞菌至关重要的 NK 细胞 IFN-γ的释放。此外，脓毒症与骨髓中驻留 DC 的丧失有关。从 sham 小鼠骨髓中耗尽驻留 DC 会导致 BMDC 的分化，类似于脓毒症小鼠的 BMDC，其在 Th1 启动中受损。因此，多微生物脓毒症后，骨髓中的 DC 前体细胞发育成调节性 DC，损害 Th1 启动和 NK 细胞活性，并介导免疫抑制。脓毒症后骨髓中缺乏驻留 DC 可能导致 DC 分化的调节。
