Book excerpt: "This doctoral thesis describes the participation of epigenetic mechanisms, and more specifically DNA methylation, in innate immune responses against pathogens.Innate immunity is the first barrier of defense against infection. Monocytes, which are part of this innate response, orchestrate the host's antimicrobial protective responses by phagocyting and releasing various inflammatory cytokines to kill microorganisms. In addition, monocytes differentiate into macrophages and dendritic cells, which are also responsible for antigenic presentation and the consequent activation of adaptive responses. In recent years, it has been described that cells of the innate system have immune memory, responding in a more effective (trained immunity) or attenuated (endotoxin tolerance) way, against second infections. It is necessary to improve our knowledge about the cellular and molecular mechanisms that take place after an infection. The immune response is highly controlled and regulated by complex networks formed by signaling cascades, transcription factors and epigenetic mechanisms, among others.Sepsis is defined as a life-threating organic dysfunction caused by a dysregulated response to infection. Immune response in sepsis is characterized by an initial systemic inflammation followed by a state of immunosuppression, in which the immune cells acquire a tolerated phenotype, thus constituting a pathological model for the study of innate memory. In this thesis, we have studied potential DNA methylation changes in monocytes from patients with sepsis. We have described for the first time the existence of DNA methylation alterations in patients with sepsis compared to healthy controls. In addition, we have observed that DNA methylation changes correlate with IL-10 and IL-6 levels, which are increased in patients with sepsis. Between genes that show altered methylation, we found some related to IL-1 and TLR signaling and the JAK/STAT pathway, relevant pathways in the immune response against infectious agents. Finally, we also found that methylation in relevant genes is associated with organ dysfunction in septic patients.In parallel, we have performed in vitro studies on monocytes after toll-like receptor (TLR) stimulation to unravel the role of DNA methylation in the acquisition of innate memory. Statistical analysis of the data revealed specific demethylation after stimulation of TLRs. We have seen how genes relevant to monocyte function and physiology are regulated by DNA demethylation. In addition, we observed an overexpression of those genes that are specifically demethylated after LPS stimulation. The study of DNA methylation during these inflammatory processes may reveal new therapeutic strategies to reverse the immune tolerance state." -- TDX.