LXR-dependent gene expression is important for macrophage survival and the innate immune response
LXR-dependent gene expression is important for macrophage survival and the innate immune response
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DOI：
10.1016/j.cell.2004.09.032
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发表时间：
2004-10-15
期刊：
影响因子：
64.5
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
--
作者：
Joseph, SB;Bradley, MN;Tontonoz, P
肝脏X受体（LXR）是核受体，在调节脂质代谢方面已建立了作用。现在，我们表明LXR信号不仅调节巨噬细胞胆固醇代谢，还会影响抗菌反应。缺乏LXR的小鼠非常容易感染细胞内细菌单核细胞增生李斯特菌（LM）。骨髓移植研究指出巨噬细胞功能是易感性的主要决定因素。当用LM挑战并在体内表现出有缺陷的细菌清除率时，LXR无效的巨噬细胞会加速凋亡。这些缺陷至少部分是由于抗凋亡因子Spalpha的调节丢失而导致的，这是lxralpha调节的直接靶标。在LM感染的情况下，巨噬细胞中Lxralpha或Spalpha的表达抑制了凋亡。我们的结果表明，LXR依赖性基因表达在先天免疫中起意外的作用，并表明共同的核受体途径介导巨噬细胞对改良的脂蛋白和细胞内病原体的反应。
The liver X receptors (LXRs) are nuclear receptors with established roles in the regulation of lipid metabolism. We now show that LXR signaling not only regulates macrophage cholesterol metabolism but also impacts antimicrobial responses. Mice lacking LXRs are highly susceptible to infection with the intracellular bacteria Listeria monocytogenes (LM). Bone marrow transplant studies point to altered macrophage function as the major determinant of susceptibility. LXR-null macrophages undergo accelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo. These defects result, at least in part, from loss of regulation of the antiapoptotic factor SPalpha, a direct target for regulation by LXRalpha. Expression of LXRalpha or SPalpha in macrophages inhibits apoptosis in the setting of LM infection. Our results demonstrate that LXR-dependent gene expression plays an unexpected role in innate immunity and suggest that common nuclear receptor pathways mediate macrophage responses to modified lipoproteins and intracellular pathogens.