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

TLDR

Innate immune memory describes functional reprogramming of monocytes and macrophages after exposure to microbial components such as lipopolysaccharide. The study applies an integrated epigenomic approach to characterize the time‑dependent molecular events underlying LPS‑induced tolerance. LPS‑treated monocytes fail to accumulate active histone marks at promoters and enhancers of lipid‑metabolism and phagocytic genes, and tolerized macrophages similarly lack active marks at promoters of tolerized genes upon re‑exposure. β‑glucan partially reverses LPS‑induced tolerance in vitro and ex vivo, restoring cytokine production in monocytes from endotoxemic volunteers and reactivating distal histone modifications and transcription of previously unresponsive genes. VIDEO ABSTRACT.

Abstract

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. VIDEO ABSTRACT.