波士顿儿童医院和哈佛医学院研究小组取得一项新突破。他们的最新研究提出了pH依赖性转录凝聚物对炎症反应的调节。2025年7月17日，国际知名学术期刊《细胞》发表了这一成果。
该课题组研究了巨噬细胞是否感知组织酸化来调节炎症反应。小组发现酸性pH以基因特异性的方式重组巨噬细胞的炎症反应。该课题组人员发现哺乳动物BRD4是细胞内pH传感器。酸性pH通过组氨酸富集的内在无序区破坏含有BRD4和MED1的转录凝聚体。至关重要的是，巨噬细胞胞内pH的降低是体外和体内调节转录凝聚的必要和充分条件，并作为负反馈调节炎症反应。总的来说，这些发现揭示了转录凝聚物中ph依赖性开关，使炎症的环境依赖性控制成为可能，这对于通过炎症成本校准炎症的大小和质量具有更广泛的意义。
据介绍，炎症是一种必要的防御反应，但它是以损害正常组织功能为代价的。是否以及如何监测炎症的负面影响在很大程度上仍然未知。组织微环境的酸化与炎症有关。
附：英文原文
Title: Regulation of inflammatory responses by pH-dependent transcriptional condensates
Author: Zhongyang Wu, Scott D. Pope, Nasiha S. Ahmed, Diana L. Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M. Anand, Elizabeth B. Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C. Kagan, Jay R. Thiagarajah, Diana C. Hargreaves, Ruslan Medzhitov, Xu Zhou
Issue&Volume: 2025-07-17
Abstract: Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
DOI: 10.1016/j.cell.2025.06.033
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00735-4