β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance

Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, β-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo β-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. [Display omitted] [Display omitted] •Epigenetic and transcriptional characterization of human macrophage tolerance•LPS-exposed monocytes fail to induce macrophage-specific downstream pathways•Monocyte-induced tolerance of macrophages can be reversed by β-glucan at the epigenetic level•In-vivo-tolerized monocytes can be reverted to a responsive phenotype ex vivo by β-glucan As part of the International Human Epigenome Consortium (IHEC), this study reveals that β-glucan reverses the state of epigenetic immune tolerance that develops after exposure to LPS and restores the ability of human macrophages to produce cytokines that are critical for anti-pathogen responses. Explore the Cell Press IHEC webportal at http://www.cell.com/consortium/IHEC.