Control of Inflammatory Response by Tissue Microenvironment

Abstract

SummaryInflammation is an essential defense response but operates at the cost of normal 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, decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensatesin vitroandin vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environmental sensing to directly control inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.HighlightsAcidic pH regulates a switch-like gene-specific inflammatory response in macrophagesAcidic pH impacts chromatin remodeling and transcription circuits to control inflammatory programsBRD4 transcriptional condensates are regulated by intracellular pH via pH-sensitive motifs located within the intrinsically disordered regionTissue inflammation decreases intracellular pH and disrupts BRD4 condensates as a negative feedback