美国哈佛医学院Ivan Zanoni研究小组报道了宿主来源的氧化磷脂对白细胞介素-10的表观遗传沉默支持对感染的致命炎症反应。相关论文于2025年7月17日发表在《免疫学》杂志上。

该课题组证明了宿主衍生的氧化磷脂（oxPLs）在小鼠和人类的微生物接触后形成。oxPLs加重炎症，但不影响病原体负担。从机制上讲，oxPLs结合并抑制AKT，增强蛋氨酸循环和表观遗传因子EZH2的活性。EZH2通过表观遗传抑制多能抗炎细胞因子IL-10，导致宿主死亡。总的来说，小组发现宿主来源的oxPLs在保护性和有害的抗菌反应之间建立了平衡，并且它们可以作为预防或治疗目标来保护宿主免受紊乱的炎症和免疫病理。

据了解，吞噬细胞通过模式识别受体检测病原体相关的分子模式，从而启动对入侵微生物的免疫。病原体遭遇并随之激活免疫系统，介导组织损伤并释放与宿主源性损伤相关的分子模式，有助于形成免疫。然而，自源因子如何被吞噬细胞感知并影响免疫反应仍然知之甚少。

附：英文原文

Title: Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

Author: Marco Di Gioia, Valentina Poli, Piao J. Tan, Roberto Spreafico, Anne Chu, Alex G. Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L.S.M. Gordts, Joseph L. Witztum, Talal A. Chatila, Janet Chou, Xu Zhou, James R. Springstead, Ivan Zanoni

Issue&Volume: 2025-07-17

Abstract: Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.

DOI: 10.1016/j.immuni.2025.06.017

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00286-9