Dang Eric V, McDonald Jeffrey G, Russell David W, Cyster Jason G
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143-0795, USA.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2017 Nov 16;171(5):1057-1071.e11. doi: 10.1016/j.cell.2017.09.029. Epub 2017 Oct 12.
Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation.
I型干扰素通过上调胆固醇25-羟化酶（Ch25h）并抑制SREBP转录因子来抑制巨噬细胞中白细胞介素-1β（IL-1β）驱动的炎症。然而，脂质代谢与IL-1β产生之间的分子联系仍不清楚。在此，我们证明巨噬细胞产生25-羟胆固醇（25-HC）是防止黑色素瘤2（AIM2）中不存在的DNA传感器蛋白激活炎性小体所必需的。我们发现，响应细菌感染或脂多糖（LPS）刺激，巨噬细胞上调Ch25h以维持对SREBP2激活和胆固醇合成的抑制。增加巨噬细胞胆固醇含量足以以晶体非依赖性但AIM2依赖性方式触发IL-1β释放。Ch25h缺陷导致胆固醇依赖性线粒体呼吸能力降低以及线粒体DNA释放到细胞质中。AIM2缺陷可挽救在Ch25h中观察到的炎性小体活性增加。因此，活化的巨噬细胞在维持线粒体完整性并防止假性AIM2炎性小体激活的抗炎回路中利用25-HC。
