30 Chapter 2 is expected to impair T cell function, and in mice inhibition of this pathway conferred protection against lethality following experimentally induced sepsis [40]. Clinical trials seeking to inhibit PD1 – PDL1 signaling in sepsis patients are under way. Contrary to lymphocytes, apoptosis of neutrophils in sepsis is delayed [2, 36]. Furthermore, the bone-marrow releases immature neutrophils which together results in high numbers of circulating neutrophils in different stages of maturation. The function of neutrophils is impaired in sepsis, with reduced chemotaxis and reactive oxygen production. Reprogramming of monocytes and macrophages Sepsis is further characterized by profound changes in the function of antigen presenting cells [2, 36]. Monocytes and macrophages demonstrate a strongly decreased capacity to release pro-inflammatory cytokines upon stimulation with bacterial agonists (a feature commonly referred to as “endotoxin tolerance”) and reduced HLA-DR expression. Notably, monocytes/macrophages do not show a general unresponsiveness, but rather are reprogrammed: after stimulation with bacterial compounds they produce equal or even increased amounts of anti-inflammatory cytokines. Correspondingly, mRNA expression levels of genes encoding pro-inflammatory mediators have been reported downregulated upon stimulation with concurrent upregulation of mRNA’s of antiinflammatory mediators [2, 36]. HLA-DR expression on monocytes has been suggested as a biomarker to select sepsis patients for immune stimulatory therapy. Epigenetic regulation of gene function likely plays a significant role in the host response to infection through suppression of proinflammatory gene expression and/ or activation of anti-inflammatory genes, thereby contributing to immune suppression [41]. Protein expression can be regulated both at the pre- and post-transcriptional level. Pretranscriptional regulation takes place on chromatin, the complex formed by the DNA double helix packaged by histones. The gene loci on chromatin can be organized in transcriptionally active “euchromatin” or transcriptionally silent “heterochromatin”. The chromatin activation state is regulated by histone modifications due to acetylation, methylation, ubiquitination and phosphorylation. For example, acetylation of lysine residues within histones usually facilitates transcription [41]. “Endotoxin tolerance” in monocytes has been linked to reduced expression of marks of open chromatin such as histone H3 lysine 4 trimethylation (H3K4me3)[42], and “endotoxin tolerant” macrophages showed enhanced levels of the repressive histone modification H3K9 dimethylation (H3K9m2) at the promoter sites of the genes encoding the proinflammatory cytokines TNF and IL-1β [43]. One mechanism by which microbial stimuli induce epigenetic gene regulation is through increased expression of the histone lysine demethylase KDM6B via NF-κB activation [44]. KDM6B primes genes for transcription and it is postulated that this promotes IL-4 maturation. The latter is a potent cytokine to counteract various proinflammatory cytokines and contributes to immune suppression. This IL-4/KDM6B axis appears to be one of the important pathways in the epigenetic regulation of macrophage activation [41]. The immune suppressive effects of sepsis can remain for months, perhaps even longer. It is hypothesized that epigenetic imprints occur both on mature immune cells in the periphery as well as progenitor cells in the bone marrow, thereby contribution to this long lasting immune suppression [41].
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