1. Academic Validation
  2. Regulation of inflammatory responses by pH-dependent transcriptional condensates

Regulation of inflammatory responses by pH-dependent transcriptional condensates

  • Cell. 2025 Jul 17:S0092-8674(25)00735-4. doi: 10.1016/j.cell.2025.06.033.
Zhongyang Wu 1 Scott D Pope 2 Nasiha S Ahmed 3 Diana L Leung 1 Yu Hong 1 Stephanie Hajjar 1 Cathleen Krabak 1 Zhe Zhong 1 Krishnan Raghunathan 4 Qiuyu Yue 1 Diya M Anand 1 Elizabeth B Kopp 2 Daniel Okin 5 Weiyi Ma 4 Ivan Zanoni 6 Jonathan C Kagan 4 Jay R Thiagarajah 7 Diana C Hargreaves 3 Ruslan Medzhitov 8 Xu Zhou 9
Affiliations

Affiliations

  • 1 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
  • 2 Department of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510, USA.
  • 3 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • 4 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 5 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
  • 6 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Immunology, Boston, MA, USA.
  • 7 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Congenital Enteropathy Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 8 Department of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510, USA; Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: ruslan.medzhitov@yale.edu.
  • 9 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: xu.zhou@childrens.harvard.edu.
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.

Keywords

BRD4; IDR; acidosis; gene expression; histidine; inflammatory response; innate immunity; macrophage; pH; transcriptional condensates.

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