Volatile anesthetics affect macrophage phagocytosis

Area of Science:

• Immunology
• Anesthesiology
• Cell Biology

Background:

• Perioperative infections, especially surgical site infections, significantly increase patient morbidity and mortality.
• Phagocytosis by macrophages is a vital immune mechanism for clearing microbial pathogens.
• The impact of common anesthetics on macrophage phagocytosis remains incompletely understood.

Purpose of the Study:

• To investigate the effects of isoflurane, sevoflurane, and propofol on macrophage phagocytic activity.
• To elucidate the underlying molecular mechanisms, focusing on the small GTPase Rap1.
• To identify potential off-target effects of volatile anesthetics.

Main Methods:

• Macrophage phagocytosis assays were conducted using RAW264.7, mouse peritoneal, and THP-1 cells with opsonized sheep erythrocytes or E. coli.
• Rap1 activation was assessed using pull-down assays.
• Anesthetic binding sites on Rap1 were investigated via photolabeling with modified anesthetics and alanine scanning mutagenesis.

Main Results:

• Isoflurane and sevoflurane significantly reduced macrophage phagocytosis by 50% at clinical concentrations.
• Propofol did not exhibit a significant effect on macrophage phagocytosis.
• Photolabeling and mutagenesis confirmed direct binding of sevoflurane to Rap1, inhibiting its activation and subsequent phagocytosis.

Conclusions:

• Isoflurane and sevoflurane attenuate macrophage phagocytosis, while propofol does not.
• Sevoflurane acts as a novel inhibitor of the small GTPase Rap1, revealing a new mechanism of action for volatile anesthetics.
• The identified sevoflurane binding site on Rap1, distinct from known functional sites, presents a potential target for developing novel Rap1 inhibitors.