The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines
The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines
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DOI：
10.1073/pnas.1106750109
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发表时间：
2012-01-10
影响因子：
11.1
通讯作者：
Loudon, Andrew S. I.
中科院分区：
文献类型：
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作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
炎症和免疫功能的昼夜变化在人类和动物的生理学和病理学中是明显的，但提供这种门控的分子机制和介导细胞类型仍然未知。通过筛选细胞因子的反应，在小鼠内毒素的挑战，在一天中的不同时间，我们发现，反应的幅度表现出明显的时间依赖性，但只有在一个子集的促炎细胞因子。通过关键时钟基因（bmal 1）的条件性靶向破坏巨噬细胞（先天免疫系统的初级效应细胞）的昼夜节律时钟机制，消除了培养细胞和体内内毒素诱导的细胞因子应答的所有时间门控。昼夜节律门控的丧失与rev-erb α表达的抑制是一致的，暗示这种核受体是生物钟和炎症通路之间的潜在联系。通过REV-ERB α活性的遗传和药理学调节，在体内和体外证实了这一发现。在rev-erb alpha（-/-）小鼠和来自这些动物的培养的巨噬细胞中，内毒素反应的昼夜节律门控丢失，尽管这些细胞内的昼夜节律性得以维持。使用显示生物钟基因振荡和节律性内毒素反应的人巨噬细胞，我们证明了施用合成的REV-ERB配体或基因敲低rev-erb α表达可有效调节促炎细胞因子IL-6的产生和释放。这项工作表明，巨噬细胞时钟提供了对内毒素的全身反应的时间门控，并将REV-ERB α鉴定为时钟和免疫功能之间的关键联系。因此，REV-ERB α可能代表人类炎症性疾病的独特治疗靶点。
Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erb alpha expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERB alpha activity. Circadian gating of endotoxin response was lost in rev-erb alpha(-/-) mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erb alpha expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERB alpha as the key link between the clock and immune function. REV-ERB alpha may therefore represent a unique therapeutic target in human inflammatory disease.