Relevance of SCFAs-induced histone acylation in neutrophils production of inflammatory mediators

Abstract

Neutrophils are the first cell to migrate and accumulate in tissues during inflammation. In addition to their ability to phagocyte and eliminate infectious agents through their antimicrobial mechanisms, they also regulate the initial inflammatory events. In the first 24-48 hours, neutrophils are the predominant cells in the inflammatory site and constitute a relevant source of cytokines and eicosanoids that regulate the activation and recruitment of other cells. SCFAs have been shown to modulate the recruitment, activation and effector functions of neutrophils. In this context, SCFAs (mainly, butyrate) modulate the production of inflammatory cytokines (including TNF-alfa, IL-12 and IL-10) in response to microbial stimulation. These effects were associated with inhibition of class I HDACs and changes in the pattern of histone acetylation. However, the molecular mechanism is unclear. Moreover, since histone acetylation is generally associated with activation of gene expression, it is intriguing that by inducing acetylation (or other acylations), SCFAs repressed the expression of TNF-alfa and IL-10. In this context, it is important to mention that other studies focused on macrophages, dendritic cells and microglia demonstrated that HDAC inhibitors have cell-specific effects on expression of genes activated by LPS/TLR4 signalling pathways. However, no information on neutrophils is available. The aim of this project is investigate the molecular mechanisms by which the SCFAs interfere with neutrophils responses to bacterial stimulation. (AU)