Regulation of LPS Tolerance in Macrophages (48.2)

Abstract

Abstract Lipopolysaccharide (LPS) tolerance is an essential immune-homeostatic response which prevents unnecessary over-activation of the inflammatory response. LPS tolerance induces a state of reduced responsiveness to repeated challenges with LPS, resulting in decreased expression of pro-inflammatory modulators, up-regulation of antimicrobials and other mediators promoting the resolution of inflammation. LPS tolerance is a transient state and LPS tolerant macrophages (MΦT) return to an LPS responsive state within days of initial stimulation. Macrophages which have recovered from a tolerant state (MΦR) remain largely uncharacterised. Gene expression profiling reveals that LPS tolerance recovery triggers an extensive modulation of the gene expression profile of macrophages distinct from that of (MΦT) and LPS activated macrophages (MΦA). Recovery from LPS tolerance at 88 hours post treatment leads to expression of key pro-inflammatory genes at levels comparable to MΦA. MΦR show increased expression of key modulators of the immune response not previously observed during classical activation. We propose that MΦR represent a novel macrophage phenotype. Furthermore we propose that the recovery from LPS tolerance promotes a global modulation of gene expression with distinct expression profiles between genes promoting inflammation and genes key to the resolution of inflammation. In addition we present an expression analysis of NF-κB and its regulators in naïve, MΦT and MΦR cells.