Western diet triggers NLRP3-dependent persistent functional reprogramming of myeloid cells [ATAC-Seq]

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 undectable in serum soon after mice were shifted back to chow diet (CD). In contrast, myeloid cell responses towards innate stimuli remained broadly augmented. WD induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells, leading to increased proliferation as well as enhanced innate immune and interferon responses towards in vivo LPS challenge. QTL analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with LPS suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/--deficient mice lacked WD-induced systemic inflammation or myeloid progenitor proliferation and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby arbitrate the potentially deleterious effects of trained immunity in inflammatory diseases. Overall design: Examination of GMPs in three different conditions by ATAC-seq

本研究旨在探究无菌性炎症触发因素是否可诱导训练免疫（trained immunity），进而影响先天免疫应答。给低密度脂蛋白受体基因敲除（Ldlr-/-）小鼠喂食西方饮食（Western diet, WD）可诱导全身性炎症；当小鼠转回常规饲料（chow diet, CD）饲养后，血清中的炎症因子很快便无法检出。与之相反，髓系细胞对先天刺激的应答仍广泛处于增强状态。西方饮食可诱导髓系祖细胞发生转录组与表观基因组重编程，不仅使其增殖能力提升，还能增强其在体内受到脂多糖（lipopolysaccharide, LPS）刺激时的先天免疫与干扰素应答。对经氧化型低密度脂蛋白（oxidized low-density lipoprotein, oxLDL）预处理并经脂多糖刺激的人单核细胞开展数量性状位点（quantitative trait locus, QTL）分析，结果显示炎症小体介导了训练免疫。与此一致的是，Nlrp3基因与Ldlr基因双敲除（Nlrp3-/-/Ldlr-/-）小鼠不会出现西方饮食诱导的全身性炎症、髓系祖细胞增殖与重编程。综上，NLRP3可介导西方饮食诱导的训练免疫，进而可在炎症性疾病中调控训练免疫潜在的有害效应。整体实验设计：通过ATAC-seq技术检测三种不同条件下的粒细胞-单核细胞祖细胞（granulocyte-monocyte progenitors, GMPs）。