Macrophages are major components of the innate immune system and play a critical role in modulating inflammatory and immune responses. Extracellular bacterial lipopolysaccharide (LPS) acts as pathogen-associated molecular pattern and is recognized by the Toll-like receptor (TLR)-4, inducing macrophages to an activated state, producing pro-inflammatory cytokines and chemokines and enhancing the expression of inflammatory-related enzymes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1, which synthesize nitric oxide (NO) and prostaglandin (PG)E2, respectively. Additionally, LPS-stimulated macrophages disrupt the balance of the intracellular reduction–oxidation state, leading to oxidative stress, usually accompanied by damage that is mediated by reactive oxygen species (ROS). The process of gene expression of these pro-inflammatory mediators involves multiple signal transduction pathways, which are mainly through mitogen-activated protein kinases (MAPKs), nuclear transcription factor-kappa B (NF-κB), janus kinase/signal transducer and transcription activator of transcription (JAK/STAT) or inflammasome activation. Furthermore, the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2)/haem oxygenase-1 (HO-1) antioxidative axis, which exerts a regulative function on the activation of ROS, MAPKs, and inflammasome signaling pathways, is repressed in the event of the induction of the activated macrophages state.
Emerging evidence suggests that epigenetic processes that affect gene expression without causing changes in the nucleotide sequence occur after external stimuli exposure, and may contribute to the pathophysiology of inflammatory processes. In particular, histone H3 methylation at lysine 9 (H3K9), one of the most conserved epigenetic markers, is correlated with gene silencing and the modulation of immune cell differentiation and immune responses, and therefore, influences the outcome of inflammation. […]
