Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages.
Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages.
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DOI：
10.1097/shk.0b013e31818ba2a2
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发表时间：
2009-04
期刊：
影响因子：
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通讯作者：
Hotchkiss RS
中科院分区：
文献类型：
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作者：
Peck-Palmer OM;Unsinger J;Chang KC;McDonough JS;Perlman H;McDunn JE;Hotchkiss RS
本研究在小鼠脓毒症模型中检测了树突状细胞（dc）和巨噬细胞（MΦ）在体内的命运。使用野生型、敲除型和转基因小鼠来研究Bcl-2家族成员在调节脾DCs和MΦ存活中的作用。使用Bim敲除（Bim−/−）小鼠和在选定的造血细胞中过表达Bcl-2的小鼠：(a)使用vav启动子在所有造血细胞中过表达Bcl-2 （vav - Bcl-2）和(b)在所有MHC I类细胞中过表达Bcl-2 （H-2K-Bcl-2）。小鼠进行假手术或盲肠结扎穿刺，测定脾dc和MΦ的绝对数量。重要的是，两个不同的MΦ群体，即分化良好的“成熟”MΦ群体和分化较低的“未成熟”，“单核细胞样”（IMΦ）群体被鉴定出对细胞凋亡的不同易感性。在野生型小鼠中，脓毒症诱导脾dc和IMΦ绝对细胞数分别减少64%±7%和77%±3% （n = 7, P < 0.05）。成熟的MΦ在败血症中未被耗尽。在Vav-Bcl-2、H-2K-Bcl-2或Bim - / -小鼠中没有明显的细胞损耗。我们得出结论，脓毒症诱导发展中的MΦ和dc的大量耗竭，这种耗竭可能是脓毒症中免疫抑制的重要机制。
This study examined the fate of dendritic cells (DCs) and macrophages (MΦ) in vivo in a murine model of sepsis. Wild-type, knockout, and transgenic mice were used to examine the role of Bcl-2 family members on the regulation of splenic DCs and MΦ survival. Bim knockout (Bim−/−) mice and mice overexpressing Bcl-2 in selected hematopoietic cells were used: (a) overexpression of Bcl-2 in all hematopoietic cells using a vav promoter (Vav–Bcl-2) and (b) overexpression of Bcl-2 in all MHC class I cells (H-2K–Bcl-2). Mice underwent sham surgery or cecal ligation and puncture, and absolute numbers of splenic DCs and MΦ were determined. Importantly, two distinct MΦ populations, that is, well-differentiated “mature” MΦ population and a less differentiated “immature,” “monocyte-like” (IMΦ) population were identified that demonstrated differential susceptibility to apoptosis. In wild-type mice, sepsis induced a 64% ± 7% and a 77% ± 3% decrease in absolute cell numbers of splenic DCs and IMΦ, respectively (n = 7, P < 0.05). Mature MΦ were not depleted in sepsis. No significant cell depletion was evident in Vav–Bcl-2, H-2K–Bcl-2, or Bim−/− mice. We conclude that sepsis induces a major depletion of developing MΦ as well as DCs, and this depletion may be an important mechanism of immune suppression in sepsis.