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An inflammatory response is a localized, nonspecific immune reaction that occurs when a tissue is injured. It is characterized by redness, swelling, heat, and pain, which are commonly called the cardinal signs and symptoms of inflammation. Inflammation can sometimes result in a loss of function.
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The inflammatory response is the body's defense against infection, injury, or irritation from bacteria, trauma, toxins, or heat. Inflammation helps locate and destroy pathogens and remove damaged tissue elements to heal the body. During this initial phase, fluid, blood products, and nutrients migrate to the injured area, resulting in redness, heat, swelling, ache, and loss of function. Moreover, signs of systemic inflammation include fever, increased WBC count, malaise, anorexia, nausea,...
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Control of Inflammatory Response by Tissue Microenvironment.

Zhongyang Wu1,2, Scott D Pope3,4, Nasiha S Ahmed5

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Macrophages sense acidic environments during inflammation. This pH sensing, mediated by BRD4, regulates gene expression and inflammatory responses, providing crucial feedback to control inflammation.

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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.