Understanding the role of cholesterol biosynthesis intermediates in establishing immune tolerance in human monocytes

Abstract

The reprogramming of monocytes to exert different effector functions is dependent on numerous cellular biological pathways. The activation of pattern recognition receptors (PRRs) upon stimulation by pathogen-associated molecular patterns (PAMPs) induces inflammatory, antimicrobial responses and promotes innate immune tolerance. The latter is a state of unresponsiveness towards antigens and pathogens, which is understood to be an adaptation of the innate immune cells to prevent tissue damage due to sustained inflammatory responses. However, if dysregulated, it could also increase the susceptibility to infection, especially those considered nosocomial. Recent research suggests that the induction of immune tolerance in monocytes may be connected to cholesterol biosynthesis. The effect of derivatives of cholesterol synthesis, specifically squalene, on the establishment of innate immune tolerance is still unknown. Therefore, this project sought to assess the cytokine production capacities of primary human monocytes before and after treatment with a cholesterol biosynthesis derivative, that is squalene, as well as in the context of a monocyte-derived macrophage immune tolerance model established by repeated exposure to Escherichia (E.) coli lipopolysaccharide (LPS). Enzyme-linked immunosorbent assays (ELISA) targeting TNFα showed squalene did not alter the cellular response to LPS, however demonstrated a trend towards promoting tolerance.