ArticleCell2025
Regulation of inflammatory responses by pH-dependent transcriptional condensates.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed.
- Activatable NIR-II photoacoustic probes for cancer imaging and imaging-guided therapy.Bioactive materials · 2026Review
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- BRD4: From molecular understanding to therapeutics development.Molecular cell · 2026Review
- Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation.Science advances · 2026Article
- Sea Urchin-Inspired Immuno-Instructive Ionic Flow Drives MSCs-Macrophage Communication to Promote Bone Regeneration.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Intracellular pH dynamics promotes zebrafish larval tail regeneration.bioRxiv : the preprint server for biology · 2026Article
- Bromodomain dimers: A case study of BRD4 and family-wide AlphaFold predictions.Structural dynamics (Melville, N.Y.) · 2026Article
- Protocol for immunofluorescence detection and quantitative analysis of pH-dependent transcriptional condensates.STAR protocols · 2026Article
- Nonthermal radiofrequency radiation promotes hematopoietic stem and progenitor cells function by regulating CaStem cell research & therapy · 2026Article
- Phase separation and the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- DNA nanodevices detect an acidic nanolayer on the lysosomal surface.Nature cell biology · 2026Article
- Macrophage sensing of the acidic milieu: BRD4 condensates in focus.Life metabolism · 2026Article
- Targeting GPR68 Alleviates Inflammation and Lipid Accumulation in Metabolic Dysfunction-Associated Steatohepatitis.Biology · 2026Article
- Novel intermolecular zinc fingers and redox-driven conformational changes dictate tumor suppressor ZMYND11's role in cooperative recognition of diverse targets.Nucleic acids research · 2026Article
- DNA co-recognition and pH dependent regulation mechanism of zinc finger domain and C-terminal basic region of CreA in Aspergillus.Archives of microbiology · 2026Article
- Condensatopathies as a mechanistic framework for disease and integrated theranostic intervention.Theranostics · 2026Review
- Nanotechnology for atherosclerotic plaque stabilisation: bridging innovation and clinical practice.EBioMedicine · 2026Review
- pH sensing and inflammation: linking acidic microenvironments to immune reprogramming.Frontiers in immunology · 2026Review
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
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Authors and funding
20 authors.
Zhongyang WuDivision 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.
Scott D PopeDepartment of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510, USA.
Nasiha S AhmedMolecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Diana L LeungDivision 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.
Yu HongDivision 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.
Stephanie HajjarDivision 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.
Cathleen KrabakDivision 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.
Zhe ZhongDivision 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.
Krishnan RaghunathanDivision of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Qiuyu YueDivision 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.
Diya M AnandDivision 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.
Elizabeth B KoppDepartment of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510, USA.
Daniel OkinDivision 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.
Weiyi MaDivision of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Ivan ZanoniDivision 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.
Jonathan C KaganDivision of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Jay R ThiagarajahDivision 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.
Diana C HargreavesMolecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Ruslan MedzhitovDepartment 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.
Xu ZhouDivision 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.
Funding
STRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4MResearch Training in Pulmonary Immunology and Allergy at MGHT32HL116275 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI David C Christiani, ANDREW D LUSTER · 2013 to 2026
$8.6MSpatial and temporal resolution to dissect cellular circuits controlling intestinal physiology, immunity, and inflammatory pathologiesRC2DK135492 · NIDDK · BROAD INSTITUTE, INC. · PI Caroline Uhler, Ramnik J Xavier · 2023 to 2026
$7.9MCenter for Open Bioimage AnalysisP41GM135019 · NIGMS · BROAD INSTITUTE, INC. · PI CARPENTER, ANNE E., CIMINI, BETH · 2020 to 2024
$6.9MThe role of BAF related complexes in regulatory T cell development and functionR01AI151123 · NIAID · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI HARGREAVES, DIANA CLARE, ZHENG, YE · 2020 to 2024
$4.0MRegulation of immunity by the cGAS-STING pathwayR01AI167993 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI JONATHAN C KAGAN · 2022 to 2026
$3.9MDefining the pathways activated by Toll-like Receptors to stimulate immunityR37AI116550 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI JONATHAN C KAGAN · 2021 to 2026
$3.3MMacrophage immunometabolism controls septic shockR01AI170632 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI Ivan Zanoni · 2023 to 2026
$2.5MDecoding Hydrogen Peroxide Signaling at Cellular Membranes (Equipment Supplement)R35GM142683 · NIGMS · BOSTON CHILDREN'S HOSPITAL · PI THIAGARAJAH, JAY · 2021 to 2025
$2.3MUnderstanding Immune-Stromal Interactions in Tissue Homeostasis and InflammationR35GM151000 · NIGMS · BOSTON CHILDREN'S HOSPITAL · PI XU ZHOU · 2023 to 2026
$1.8MNHLBI NIH HHS T32 HL116275NIAID NIH HHS R01 AI151123NIAID NIH HHS R01 AI167993NIAID NIH HHS R01 AI170632NIAID NIH HHS R37 AI116550NIDDK NIH HHS P30 DK034854NIDDK NIH HHS RC2 DK135492NIGMS NIH HHS P41 GM135019NIGMS NIH HHS R35 GM142683NIGMS NIH HHS R35 GM151000
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.
Indexed as
Biomolecular CondensatesInflammationTranscription FactorsAnimalsBromodomain Containing ProteinsCell Cycle ProteinsHumansHydrogen-Ion ConcentrationMacrophagesMiceMice, Inbred C57BLNuclear ProteinsRAW 264.7 CellsTranscription, GeneticBrd4 protein, mouseBromodomain Containing ProteinsCell Cycle ProteinsNuclear ProteinsTranscription FactorsacidosisBRD4gene expressionhistidineIDRinflammatory responseinnate immunitymacrophagepHtranscriptional condensates
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