Control of Inflammatory Response by Tissue Microenvironment

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Inflammation is a critical defense mechanism but can impair normal physiological functions.
• The mechanisms by which the negative consequences of inflammation are monitored are not well understood.
• Tissue microenvironment acidification is a known hallmark of inflammation.

Purpose of the Study:

• To investigate if macrophages can sense tissue acidification to modulate inflammatory responses.
• To identify molecular mechanisms linking pH changes to inflammatory gene regulation.

Main Methods:

• Macrophage cell cultures and in vivo models were used to study inflammatory responses.
• Gene expression analysis and biochemical assays were employed to assess pH-dependent effects.
• Investigated the role of Bromodomain-containing protein 4 (BRD4) in pH sensing.

Main Results:

• Acidic pH restructured macrophage inflammatory gene expression in a specific manner.
• Mammalian Bromodomain-containing protein 4 (BRD4) was identified as a novel intracellular pH sensor.
• Acidic pH disrupts transcription condensates containing BRD4 and MED1 through histidine-rich regions.
• Decreased macrophage intracellular pH regulates transcriptional condensates in vitro and in vivo, providing negative feedback.

Conclusions:

• Uncovered a pH-dependent switch in transcriptional condensates that links environmental sensing to direct control of inflammation.
• Demonstrated that intracellular pH decrease in macrophages is essential for regulating inflammatory responses.
• Findings suggest a broader implication for calibrating inflammation magnitude and quality based on inflammatory cost.