Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis.
Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis.
复制标题
DNA 甲基化的改变是脓毒症中单核细胞失调和先天衰竭记忆的基础。
DOI：
10.1101/2023.08.30.555580
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Li,Liwu
中科院分区：
文献类型：
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作者：
Caldwell,BlakeA;Wu,Yajun;Wang,Jing;Li,Liwu
先天免疫记忆是病原体暴露引起细胞内在状态以改变未来免疫挑战强度的过程。这种改变的记忆状态驱动脓毒症期间单核细胞失调，促进以促炎、免疫抑制基因表达为特征的致病行为，并与紧急造血相一致。表观遗传变化，特别是以组蛋白修饰的形式，已被证明是先天免疫记忆的基础，但DNA甲基化对这一过程的贡献仍然知之甚少。使用缺氧体内脓毒症模型，我们发现整个衰竭单核细胞基因组中DNA甲基化的广泛变化，包括先前被认为是脓毒症和Covid-19感染期间免疫失调的主要驱动因素的几个基因（例如plac8）。甲基组改变部分是由耗竭单核细胞中的Wnt信号抑制所驱动的，并且可以通过DNA甲基转移酶抑制剂、Wnt激动剂或免疫训练分子治疗来逆转。重要的是，这些变化在盲肠浆液注射后的脓毒症小鼠中重现，导致关键免疫基因的稳定变化，支持DNA甲基化参与脓毒症期间急性和长期单核细胞失调。
Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using anex vivosepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g.Plac8). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.