Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2.
Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2.
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DOI：
10.1073/pnas.1800431115
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发表时间：
2018-09-04
影响因子：
11.1
通讯作者：
Curtis AM
中科院分区：
文献类型：
--
作者：
Early JO;Menon D;Wyse CA;Cervantes-Silva MP;Zaslona Z;Carroll RG;Palsson-McDermott EM;Angiari S;Ryan DG;Corcoran SE;Timmons G;Geiger SS;Fitzpatrick DJ;O'Connell D;Xavier RJ;Hokamp K;O'Neill LAJ;Curtis AM
分子钟提供了一种预测机制，使生物体能够对外部环境的日常变化做出准备和反应。先天免疫系统对病原体威胁的反应取决于一天中的时间;然而，这背后的分子机制尚未完全揭示。我们观察到，核心分子时钟成分BMAL 1在促进骨髓细胞的抗氧化反应中至关重要。巨噬细胞中Bmal 1的缺失破坏了NRF 2的活性，促进了活性氧和促炎细胞因子IL-1β的积累。因此，分子钟直接控制NRF 2转录活性和抗氧化能力，以调节髓样细胞中的IL-1β。多种先天免疫反应和功能取决于一天中的时间，许多炎症性疾病与免疫细胞内分子钟功能失调有关。然而，这些先天免疫时钟的功能重要性尚未得到充分的表征。NRF 2在先天免疫系统中起关键作用，通过活性氧（ROS）抑制和直接抑制促炎细胞因子IL-1β和IL-6来限制炎症。在这里，我们揭示了核心分子时钟蛋白，BMAL 1，控制Nrf 2的mRNA表达，通过直接的E-box结合到其启动子，以调节其活性。Bmal 1的缺失降低了NRF 2对LPS攻击的反应，导致抗氧化反应减弱和谷胱甘肽合成减少。ROS在Bmal 1 −/−巨噬细胞中的积累增加，促进缺氧反应蛋白HIF-1α的积累。在缺乏BMAL 1的细胞中，ROS和HIF-1α水平的增加以及NRF 2活性的降低导致促炎细胞因子IL-1β的产生增加。Bmal 1 −/−巨噬细胞的过度促氧化和促炎表型通过NRF 2的遗传和药理学激活或通过添加抗氧化剂来拯救。我们的研究结果揭示了分子时钟在调节先天免疫细胞中的NRF 2以控制炎症反应中的明确作用。这些发现为炎症性疾病的病理学提供了见解，已知分子钟、氧化应激和IL-1β在其中发挥作用。
The molecular clock provides an anticipatory mechanism, allowing organisms to prepare and respond to daily changes in the external environment. The response of the innate immune system to pathogenic threats is dependent on time of day; however, the molecular mechanisms underlying this have yet to be fully uncovered. We observe that the core molecular clock component, BMAL1, is crucial in promoting an antioxidant response in myeloid cells. Deletion of Bmal1 in macrophages disrupts NRF2 activity, facilitating accumulation of reactive oxygen species and the proinflammatory cytokine, IL-1β. Thus the molecular clock directly controls NRF2 transcriptional activity and antioxidant capacity to regulate IL-1β in myeloid cells. A variety of innate immune responses and functions are dependent on time of day, and many inflammatory conditions are associated with dysfunctional molecular clocks within immune cells. However, the functional importance of these innate immune clocks has yet to be fully characterized. NRF2 plays a critical role in the innate immune system, limiting inflammation via reactive oxygen species (ROS) suppression and direct repression of the proinflammatory cytokines, IL-1β and IL-6. Here we reveal that the core molecular clock protein, BMAL1, controls the mRNA expression of Nrf2 via direct E-box binding to its promoter to regulate its activity. Deletion of Bmal1 decreased the response of NRF2 to LPS challenge, resulting in a blunted antioxidant response and reduced synthesis of glutathione. ROS accumulation was increased in Bmal1−/− macrophages, facilitating accumulation of the hypoxic response protein, HIF-1α. Increased ROS and HIF-1α levels, as well as decreased activity of NRF2 in cells lacking BMAL1, resulted in increased production of the proinflammatory cytokine, IL-1β. The excessive prooxidant and proinflammatory phenotype of Bmal1−/− macrophages was rescued by genetic and pharmacological activation of NRF2, or through addition of antioxidants. Our findings uncover a clear role for the molecular clock in regulating NRF2 in innate immune cells to control the inflammatory response. These findings provide insights into the pathology of inflammatory conditions, in which the molecular clock, oxidative stress, and IL-1β are known to play a role.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
16.6
作者：
Sutton CE;Finlay CM;Raverdeau M;Early JO;DeCourcey J;Zaslona Z;O'Neill LAJ;Mills KHG;Curtis AM
通讯作者：
Curtis AM
淋巴细胞昼夜节律的时钟控制淋巴结运输和适应性免疫反应。
影响因子：
32.4
作者：
Druzd D;Matveeva O;Ince L;Harrison U;He W;Schmal C;Herzel H;Tsang AH;Kawakami N;Leliavski A;Uhl O;Yao L;Sander LE;Chen CS;Kraus K;de Juan A;Hergenhan SM;Ehlers M;Koletzko B;Haas R;Solbach W;Oster H;Scheiermann C
通讯作者：
Scheiermann C
影响因子：
10.5
作者：
Pekovic-Vaughan V;Gibbs J;Yoshitane H;Yang N;Pathiranage D;Guo B;Sagami A;Taguchi K;Bechtold D;Loudon A;Yamamoto M;Chan J;van der Horst GT;Fukada Y;Meng QJ
通讯作者：
Meng QJ
DOI：
10.1096/fj.201600353r
发表时间：
2016-11
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Hand LE;Hopwood TW;Dickson SH;Walker AL;Loudon AS;Ray DW;Bechtold DA;Gibbs JE
通讯作者：
Gibbs JE