TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-α autocrine signalling
TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-α autocrine signalling
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DOI：
10.4049/jimmunol.178.6.3731
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Knaus, Ulla G.
中科院分区：
文献类型：
--
作者：
Lombardo, Eleuterio;Alvarez-Barrientos, Alberto;Knaus, Ulla G.
巨噬细胞存活的调节是炎症反应消退的关键因素。暴露于LPS保护先天免疫细胞免于凋亡，尽管负责延长巨噬细胞存活的精确途径仍有待完全建立。本研究的目的是更详细地描述M-CSF撤出后TLR 4介导的小鼠骨髓源性巨噬细胞存活的机制。使用基因敲除小鼠和药理学抑制剂的组合使我们能够表明TLR 4和TLR 2刺激以MyD 88-、PI 3 K-、ERK-和NF-κ B依赖性方式促进巨噬细胞的长期存活。LPS诱导的长期而非短期生存需要通过TNF-α的自分泌信号传导，并通过一般的细胞保护程序促进，类似于M-CSF介导的。TLR 4介导的巨噬细胞存活伴随着特异性细胞表面标志物的显著上调，表明LPS刺激导致巨噬细胞向混合巨噬细胞/树突状细胞样表型分化。
Modulation of macrophage survival is a critical factor in the resolution of inflammatory responses. Exposure to LPS protects innate immune cells against apoptosis, although the precise pathways responsible for prolongation of macrophage survival remain to be fully established. The goal of this study was to characterize the mechanism of TLR4-mediated survival of murine bone marrow-derived macrophages upon M-CSF withdrawal in more detail. Using a combination of knockout mice and pharmacological inhibitors allowed us to show that TLR4 and TLR2 stimulation promotes long-term survival of macrophages in a MyD88-, PI3K-, ERK-, and NF-kappa B-dependent manner. LPS-induced long-term, but not short-term, survival requires autocrine signaling via TNF-alpha and is facilitated by a general cytoprotective program, similar to that mediated by M-CSF. TLR4-mediated macrophage survival is accompanied by a remarkable up-regulation of specific cell surface markers, suggesting that LPS stimulation leads to the differentiation of macrophages toward a mixed macrophage/dendritic cell-like phenotype.