Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABA_A receptor and dysregulation of p130cas phosphorylation

Abstract

Surgical stress and anesthesia result in systemic immunosuppression. Propofol, a commonly used anesthetic agent, alters immune cell functions. Previously, we demonstrated that extracellular pressure increases macrophage phagocytosis. We hypothesized that propofol might influence pressure-induced macrophage phagocytosis in monocytes from patients undergoing surgery. Pressure (20 mmHg above ambient pressure) augmented phagocytosis in monocytes from non-propofol-anesthetized patients but reduced phagocytosis in monocytes from propofol-anesthetized patients. In vitro, propofol stimulated phagocytosis but reversed pressure-induced phagocytosis in THP-1 macrophages and monocytes from healthy volunteers. The GABAA receptor antagonists picrotoxin and SR-95531 did not affect basal THP-1 phagocytosis or prevent pressure-stimulated phagocytosis. However, picrotoxin and SR-95531 negated the inhibitory effect of pressure in propofol-treated cells without altering propofol-induced phagocytosis. Phosphorylation of the adaptor protein p130cas was inversely related to phagocytosis: it was inhibited by pressure or propofol but increased by pressure + propofol compared with propofol alone. Reduction of p130cas by small interfering RNA in THP-1 macrophages increased basal phagocytosis and prevented pressure and propofol effects. In conclusion, propofol may alter macrophage responses to pressure via the GABAA receptor and p130cas, whereas pressure also acts via p130cas but independently of GABAA receptors. p130cas may be an important target for modulation of macrophage function in anesthetized patients.

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

“…Through the activation of the GABA receptors, propofol exerts various pharmacological effects, including the inhibition of chemotaxis, phagocytosis, ROS generation, and/or cytokine synthesis in monocytes and macrophages (8,9). Another research has demonstrated that human neutrophils express GABA B , but few GABA A receptors (41).…”

“…It is noteworthy that propofol suppresses chemotaxis, phagocytosis, the generation of reactive oxygen species (ROS), and/or the synthesis of cytokines by monocytes and macrophages, which are mediated by activation of the g-aminobutyric acid (GABA) A receptor (8,9); reduces the mitochondria potential (10); and inhibits the AKT/IKKb/NF-kB pathways (11). Propofol impairs the chemotaxis and respiratory burst of neutrophils in response to fMLF (12,13).…”

Propofol’s effects on phagocytosis, proliferation, nitrate production, and cytokine secretion in pressure-stimulated microglial cells

“…27–29 We previously also reported that propofol (2,6-diisopropylphenol) stimulates macrophage phagocytosis but reverses pressure-stimulated macrophage phagocytosis. 30 Propofol is known to alter the functions of immunocompetent cells as well as to decrease pro-inflammatory cytokine production and iNOS expression in LPS-stimulated mouse macrophages. 31–33 .…”

Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections

“…As monocytes are not as efficient in performing the effector functions of macrophages, including phagocytosis of dead cells (62,63), it is possible that propofol exposure resulted in the uncontrolled expansion of neutrophilic abscesses as a result of reduced macrophage populations and the associated reduction in the phagocytosis of neutrophil corpses. In addition to the drug's potential effects on monocyte differentiation, in vitro studies have shown that exposure to propofol decreases phagocytosis of latex beads in human microglial cell culture (64) and in human THP-1 macrophage cell lines (26). We speculate that the combined effects of propofol on inhibition of monocyte differentiation and impaired phagocytosis contribute to the diffuse and extensive abscess formation observed in the kidneys of drug-treated animals.…”