KSHV vIL-6通过表观遗传重编程来增强炎症反应.
Tomoki Inagaki1, Kang-Hsin Wang1, Ashish Kumar1
1Department of Dermatology, School of Medicine, the University of California Davis (UC Davis), Sacramento, California, United States of America.
PLoS pathogens
|November 7, 2023
概括
卡波西肉瘤相关的疹病毒 (KSHV) 炎症性细胞因子综合征 (KICS) 涉及高病毒载荷和高细胞因子. 长时间暴露于病毒IL-6 (vIL-6) 会产生表观遗传记忆,增加炎症风险.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 卡波西肉瘤相关性疹病毒 (KSHV) 炎症性细胞因子综合征 (KICS) 是一种与KSHV感染相关的慢性炎症性疾病.
- KICS的特点是高KSHV病毒载量和病毒IL-6 (vIL-6) 和人类IL-6 (hIL-6) 的血清水平升高.
- 长时间暴露于vIL-6被怀疑会推动疾病的进展,但其精确的生物效应尚未完全理解.
研究的目的:
- 调查长时间暴露于vIL-6对染色质景观和随后的细胞因子产生的影响.
- 阐明vIL-6影响单细胞炎症反应的分子机制.
- 评估BRD4抑制剂在缓解vIL-6驱动炎症方面的治疗潜力.
主要方法:
- 使用醇 (SH) 相关化进行代谢测序 (SLAM) 和Cleave Under Target & Release Using Nuclease (CUT&RUN) 分析.
- 检查的染色质修饰,包括基因素乙化和转录因子结合 (BRD4,NF-κB p65).
- 评估了细胞因子的产生 (hIL-6,IL-10) 和BRD4抑制剂的作用 (OTX015,MZ1).
主要成果:
- 长时间的vIL-6暴露增加了BRD4和乙化组合素H3K27在染色质上的同时占用,通常与平衡的RNA聚合酶II结合在一起.
- 增强的BRD4招募导致刺激后增加和持续的NF-κB p65结合,促进快速和长时间的转录爆发.
- 这导致hIL-6和IL-10的产量增加,而BRD4抑制剂可以逆转这种情况.
结论:
- 持续的vIL-6暴露会为单细胞中的炎症反应建立一个容许的染色质景观.
- 这种由BRD4和NF-κB驱动的表观遗传记忆可能解释了KSHV感染个体患慢性炎症疾病的风险增加.
- 通过阻断vIL-6诱导的炎症性细胞因子产生,BRD4抑制为KICS提供了潜在的治疗策略.
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