The Role of the MEK1/2-ERK-RSK Signalling Axis in Innate Immune Memory
Abstract
Macrophages are innate immune cells that change their cellular states in response to different stimuli. This process is referred to as “innate immune memory” which can render two polarizing states: hyporesponsive (tolerated) or hyperresponsive (trained) states. To date, epigenetic modifications were shown to play a key role in innate immune memory. However, the signalling that induces memory is poorly understood. In this study, I examined the effects of various inhibitors targeting key signalling molecules involved in the activation of macrophages by the Gram-negative cell wall component lipopolysaccharide. I found that prolonged inhibition of the MEK1/2-ERK-RSK signalling axis prevented tolerance and trained macrophages in expressing inflammatory cytokines. Through transcriptomic and biochemical analyses, I showed that inhibition of the signalling axis trained macrophages in part by relieving the gene repression mediated by histone 3 in lysine 9 methylation. This study unravelled a novel role of the signalling axis in innate immune memory.