Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA.
Department for Genomics & Immunoregulation, and Myeloid Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.
Cell. 2018 Jan 11;172(1-2):162-175.e14. doi: 10.1016/j.cell.2017.12.013.
Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3/Ldlr mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.
长期以来，固有免疫细胞对微生物的表观遗传重编程（也称为“训练性免疫”）导致细胞功能发生持久改变，以防止二次感染。在这里，我们研究了无菌性炎症触发是否会诱导训练性免疫，并由此影响固有免疫反应。载脂蛋白 E 基因敲除（Ldlr）小鼠的西方饮食（WD）喂养会引起全身炎症，但在这些小鼠转回标准饮食（CD）后，血清中的炎症很快就消失了。相比之下，髓系细胞对固有刺激的反应仍然广泛增强。WD 诱导的髓系祖细胞的转录组和表观遗传重编程导致增殖增加和固有免疫反应增强。用氧化型低密度脂蛋白（oxLDL）和脂多糖（LPS）训练的人单核细胞的数量性状基因座（QTL）分析表明，炎症小体介导的训练性免疫。一致地，Nlrp3/Ldlr 小鼠缺乏 WD 诱导的全身炎症、髓系祖细胞增殖和重编程。因此，NLRP3 介导 WD 后的训练性免疫，并且可能介导训练性免疫在炎症性疾病中的潜在有害作用。
