Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness

Area of Science:

• Immunology
• Cell Biology
• Metabolic Physiology

Background:

• Severe sepsis causes organ hypofunction and immunosuppression.
• Acidic extracellular pH (pHe) occurs in tissue interstitial fluid during sepsis.
• Macrophage dysfunction contributes to sepsis pathology.

Purpose of the Study:

• To investigate if low extracellular pH (pHe) induces reversible metabolic and functional changes in mouse peritoneal macrophages.
• To understand the role of pH in macrophage adaptation during sepsis.

Main Methods:

• Culturing mouse peritoneal macrophages at normal and acidic pHe.
• Measuring ATP production, substrate utilization (glucose, fatty acids, glutamine, lactate).
• Assessing mitochondrial function (mass, oxygen consumption, respiratory capacity).
• Evaluating immune responses (LPS stimulation, phagocytosis) and M2-like polarization.

Main Results:

• Macrophages in acidic medium utilized less glucose and exogenous fatty acids for ATP production.
• Lactate, glutamine, and de novo fatty acids supported ATP production via enhanced mitochondrial function.
• Cells shifted to an M2-like state with altered LPS response and reduced phagocytosis.
• Normal pHe restored basal energy production, mitochondrial function, and pro-inflammatory response.

Conclusions:

• Low pHe induces adaptive metabolic changes in macrophages, supporting cell survival.
• These adaptations lead to reduced pro-inflammatory capacity and phagocytosis, contributing to sepsis-induced immunoparalysis.
• Macrophage response to low interstitial pH may explain reversible organ hypofunction in sepsis.