The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism
The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism
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DOI：
10.1016/j.celrep.2017.01.007
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发表时间：
2017-01-31
期刊：
影响因子：
8.8
通讯作者：
Valledor, Annabel F.
中科院分区：
文献类型：
--
作者：
Matalonga, Jonathan;Glaria, Estibaliz;Valledor, Annabel F.
巨噬细胞对入侵的微生物发挥有效的效应功能，但矛盾的是，它构成了许多细菌菌株复制的优先生态位。使用鼠伤寒沙门氏菌感染的模型，我们已经确定了由核受体LXR调节的分子机制，其通过多功能酶CD 38的转录激活限制宿主巨噬细胞的感染。LXR激动剂以CD 38依赖性方式降低NAD（+）的细胞内水平，抵消病原体诱导的巨噬细胞形态和F-肌动蛋白细胞骨架分布的变化，并降低非调理沙门氏菌感染巨噬细胞的能力。值得注意的是，使用LXR激动剂的药物治疗改善了与体内沙门氏菌感染相关的临床体征，并且这些作用依赖于骨髓源性细胞中的CD 38表达。总而言之，这项工作揭示了CD 38在细菌-宿主细胞相互作用中的未被重视的作用，该作用可以通过激活LXR途径来间接利用。
Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD(+) in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bonemarrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.