The contribution of the cholesterol biosynthesis pathway to complement mediated antimicrobial response in immune-tolerant human monocytes

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This syndrome is characterised by two seemingly opposing responses manifesting simultaneously, that is sustained excessive inflammation, and immunosuppression that leaves the host susceptible to secondary infections. The mechanisms underlying sepsis-induced immunosuppression are not fully understood. Recent studies have identified the cholesterol biosynthesis pathway as a modulator of trained immunity, and immune tolerance in monocytes. The latter phenomenon of immune tolerance, manifesting impaired cytokine production capacities, is advocated as a potential mechanism of immunosuppression. Notably, immune tolerance was also correlated to elevated expression of genes involved in complement pathway in monocytes purified from community acquired pneumonia patients. The study hypothesis is that the complement pathway genes are induced during immune tolerance and modulated by cholesterol biosynthesis in monocytes. To test this hypothesis, the study described herein tested the inducibility of complement factor 2 gene (C2) in the context of immune tolerance, established by repeated exposure of primary human monocytes to lipopolysaccharide (LPS), with and without a pharmacological inhibitor of cholesterol biosynthesis, Fluvastatin. TNF-α secretion was quantified and used as a measure of immune cell function. The study showed that the expression of C2 was not induced in immunotolerized nor non-immunotolerized cells on exposure to LPS. The study also showed inconclusive results on the effect of the cholesterol biosynthesis pathway on the induction of immune (endotoxin) tolerance, as is notable by the nonstatistically significant downward trend when comparing TNF-α levels produced from Fluvastatin treated cells to their non-treated counterparts.