The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia.
The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia.
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DOI：
10.1038/ncomms13944
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发表时间：
2017-01-11
影响因子：
16.6
通讯作者：
Ray P
中科院分区：
文献类型：
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作者：
Chakraborty K;Raundhal M;Chen BB;Morse C;Tyurina YY;Khare A;Oriss TB;Huff R;Lee JS;St Croix CM;Watkins S;Mallampalli RK;Kagan VE;Ray A;Ray P
细菌性肺炎是全球范围内的重大医疗负担。感染后未能解决炎症会加重肺损伤，并增加发病率和死亡率。革兰氏阴性菌在肺炎中很常见，并且可以在肺中检测到线粒体损伤相关分子模式（DAMP）心磷脂水平的增加。在这里，我们表明，小鼠感染肺炎克雷伯氏菌发展肺损伤与心磷脂的积累。心磷脂通过抑制肺CD 11b + Ly 6 GintLy 6CloF 4/80+细胞产生抗炎性IL-10来抑制炎症消退。心磷脂诱导PPARγ SUMO化，导致抑制性NCOR/HDAC 3复合物募集至IL-10启动子，但不募集至TNF启动子，从而使平衡倾向于炎症而非消退。丁酸钠对HDAC活性的抑制增强了乙酰化组蛋白3向IL-10启动子的募集，并增加了肺中IL-10的浓度。这些发现确定了肺炎期间持续性炎症的机制，并表明HDAC抑制作为治疗的潜力。由于过度活跃的炎症，未消退的细菌性肺炎导致肺组织损伤。在这里，作者表明，线粒体DAMP心磷脂通过SUMO化PPARγ促进辅阻遏物NCOR/HDAC 3复合物与IL-10启动子的结合而导致持续性炎症。
Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy. Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.