Macrophages sense tissue acidification during inflammation through BRD4, a novel intracellular pH sensor whose histidine-enriched intrinsically disordered region mediates pH-dependent dissolution of transcriptional condensates with MED1, thereby establishing a negative feedback mechanism that selectively represses enhancer-dependent inflammatory genes coordinating adaptive immunity while preserving innate antimicrobial responses.

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 a novel intracellular pH sensor. Acidic pH disrupts the 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.

Highlights

Acidic pH regulates a switch-like gene-specific inflammatory response in macrophages

Acidic pH impacts chromatin remodeling and transcription circuits to control inflammatory programs

BRD4 transcriptional condensates are regulated by intracellular pH via the histidine-enriched intrinsically disordered region

Tissue inflammation decreases intracellular pH and disrupts BRD4 condensates as a negative feedback