Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis

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 and emergency hematopoiesis. Epigenetic changes, notably via histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes implicated in immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. These changes are recapitulated in septic mice following cecal slurry injection, supporting the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.

固有免疫记忆（innate immune memory）指病原体暴露触发细胞内在状态，以改变后续免疫攻击响应强度的过程。此类改变的记忆状态会在脓毒症期间引发单核细胞功能失调，表现出促炎、免疫抑制性基因表达及应急造血特征的致病表型。表观遗传改变（epigenetic changes），尤其是组蛋白修饰（histone modifications），已被证实是固有免疫记忆的分子基础，但DNA甲基化（DNA methylation）的相关贡献仍有待阐明。本研究通过体外（ex vivo）脓毒症模型，发现耗竭单核细胞的全基因组DNA甲基化存在广泛改变，涉及多个与脓毒症及Covid-19感染期间免疫失调相关的基因（如Plac8）。耗竭单核细胞的甲基化组重编程（methylome reprogramming）部分由Wnt信号通路（Wnt signaling）抑制所驱动，且可通过DNA甲基转移酶抑制剂（DNA methyltransferase inhibitors）、Wnt激动剂（Wnt agonists）或免疫训练分子进行逆转。该类改变在盲肠内容物注射（cecal slurry injection）后的脓毒症小鼠模型中得以重现，证实DNA甲基化参与了脓毒症期间急性及长期的单核细胞功能失调过程。