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Prolonged triglyceride storage in macrophages: pHo trumps pO2 and TLR4
Mingfang Lu1, Terry Kho1, Robert S Munford2
1Antibacterial Host Defense Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Lipid-laden macrophages contribute to pathologies as diverse as atherosclerosis and tuberculosis. Three common stimuli are known to promote macrophage lipid storage: low tissue oxygen tension (pO2), low extracellular pH (pHo), and exposure to agonists such as bacterial LPS. Noting that cells responding to low pO2 or agonistic bacterial molecules often decrease pHo by secreting lactic and other carboxylic acids, we studied how pHo influences the stimulation of triacylglycerol (TAG) storage by low pO2 and LPS. We found that TAG retention after incubation for 48-72 h was inversely related to pHo when primary macrophages were cultured in 21% oxygen, 4% oxygen, or with LPS at either oxygen concentration. Maintaining pHo at ~7.4 was sufficient to prevent the increase in prolonged TAG storage induced by either low pO2 or LPS. The strong influence of pHo on TAG retention may explain why lipid-laden macrophages are found in some tissue environments and not in others. It is also possible that other long-term cellular changes currently attributed to low pO2 or bacterial agonists may be promoted, at least in part, by the decrease in pHo that these stimuli induce.
Insights
Extracellular pH (pHo) significantly impacts macrophage lipid storage. Maintaining a normal pHo (~7.4) prevents excessive triacylglycerol (TAG) accumulation, even with low oxygen or LPS stimulation, revealing pH
Area of Science:
- Cellular Biology
- Immunology
- Pathophysiology
Background:
- Lipid-laden macrophages are implicated in diseases like atherosclerosis and tuberculosis.
- Macrophage lipid accumulation is influenced by low oxygen tension (pO2), low extracellular pH (pHo), and lipopolysaccharide (LPS).
- Cellular responses to low pO2 and LPS often involve a decrease in pHo due to acid secretion.
Purpose of the Study:
- To investigate the role of extracellular pH (pHo) in modulating triacylglycerol (TAG) storage stimulated by low pO2 and LPS.
- To determine if maintaining a normal pHo can prevent excessive lipid accumulation in macrophages under these conditions.
Main Methods:
- Primary macrophages were cultured under varying oxygen concentrations (21% and 4%) and with or without LPS.
- Extracellular pH (pHo) was modulated during incubation.
- Triacylglycerol (TAG) retention was measured after 48-72 hours.
Main Results:
- TAG retention in macrophages was inversely related to extracellular pH (pHo) under both low and normal oxygen conditions.
- LPS stimulation also led to increased TAG retention, which was dependent on extracellular pH (pHo).
- Maintaining extracellular pH (pHo) at approximately 7.4 effectively prevented the prolonged TAG storage induced by low pO2 or LPS.
Conclusions:
- Extracellular pH (pHo) is a critical regulator of macrophage triacylglycerol (TAG) storage.
- The observed inverse relationship between pHo and TAG retention may explain the presence of lipid-laden macrophages in specific tissue microenvironments.
- Decreased pHo, induced by stimuli like low oxygen or LPS, may contribute to cellular changes previously attributed solely to these stimuli.
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