Macrophage signaling and function are regulated by distinct sterol biochemistries

Area of Science:

• Cell Biology
• Biochemistry
• Immunology

Background:

• Cellular membranes dynamically reorganize lipid components, including sterols, to regulate rigidity for essential functions like endocytosis.
• Diseases affecting cholesterol biosynthesis lead to low cellular cholesterol and accumulation of precursor sterols, with poorly understood consequences for membrane function and signaling.

Purpose of the Study:

• To investigate the impact of altered sterol content on macrophage signaling and membrane function.
• To explore the cellular consequences of disease-associated sterol changes in eukaryotic cells.

Main Methods:

• Utilized bone marrow-derived macrophages (BMDMs) and pharmacological inhibition of cholesterol biosynthetic enzymes.
• Analyzed cell surface protein expression, macropinocytosis, and performed transcriptomic analyses.
• Examined BMDMs from mouse models of Smith-Lemli-Opitz syndrome (SLOS).

Main Results:

• Reduced cholesterol and increased sterol intermediates impaired cell surface protein expression and macropinocytosis.
• Macropinocytic activity was sensitive to plasma membrane cholesterol levels and specific sterol modifications.
• Transcriptomic analysis revealed altered immune and chemokine signaling pathways, dysregulated vesicular sorting, and elevated endosomal/lysosomal markers.
• Impaired endosome expression and macropinocytosis were observed in SLOS model BMDMs.

Conclusions:

• Sterol imbalance significantly impacts macrophage membrane dynamics and immune cell function.
• Altered sterol content disrupts essential cellular processes, including macropinocytosis and vesicular transport.
• Findings link sterol biosynthesis disorders to impaired immune cell function and signaling.