Gene-Specific Epigenetic Regulation in Serious Infections with Systemic Inflammation

Abstract

Inflammation is a fundamental biologic process that is evolutionally conserved by a germ line code. The interplay between epigenetics and environment directs the code into temporally distinct inflammatory responses, which can be acute or chronic. Here, we discuss the epigenetic processes of innate immune cells during serious infections with systemic inflammation in four stages: homeostasis, incitement, evolution, and resolution. We describe feed-forward loops of serious infections with systemic inflammation that create gene-specific silent facultative heterochromatin and active euchromatin according to gene function, and speculate on the role of epigenetics in survival.

NAD+-dependent SIRT1 Deacetylase Participates in Epigenetic Reprogramming during Endotoxin Tolerance

“…Finally, SIRT1 itself has diverse nonnuclear functions that may impact inflammation regulation (37,38). It enhances autophagy as an alternate energy compartment, modifies circadian rhythm, enhances antioxidant production, and promotes mitochondrial biogenesis, all of which are prominent features of endotoxin tolerance (3). Taken together, this study and others support that the sirtuin family may link energy and inflammation by distinct spatial and temporal processes among diverse cell types.…”

“…Although the THP-1 cell model of endotoxin tolerance has been faithful in predicting what happens in human and animal sepsis (3,5), interpretations of this model alone require caution. To support application of the cell model to the epigenetics of human acute systemic inflammation, we previously demonstrated gene-specific formation of facultative heterochromatin at the TNF-␣ and IL-1␤ promoters in both THP-1 cells and in human blood leukocytes from human sepsis (5).…”

“…The first process occurs when epigenetic alterations reprogram distinct functional sets of genes to both activate and repress transcription of hundreds of genes (1,2); this transcriptome reprogramming generates the phenomenon known as endotoxin tolerance (3). Endotoxin tolerance requires TLR 3 receptor signaling of NFB master regulator, which first induces and then represses rapid response and potentially autotoxic proinflammatory TNF-␣ and IL-1␤.…”

“…The first process occurs when epigenetic alterations reprogram distinct functional sets of genes to both activate and repress transcription of hundreds of genes (1,2); this transcriptome reprogramming generates the phenomenon known as endotoxin tolerance (3). Endotoxin tolerance requires TLR 3 receptor signaling of NFB master regulator, which first induces and then represses rapid response and potentially autotoxic proinflammatory TNF-␣ and IL-1␤. To control the initial recognition and response phases induced by TLR, gene-specific reprogramming selectively modifies chromatin structure and shifts nucleosomes on responsive euchromatin to form silent heterochromatin at acute proinflammatory genes; in contrast, genes encoding anti-inflammatory and antimicrobial mediators maintain responsive euchromatin (4,5).…”

“…This gene set-selective reprogramming generates a clinically relevant phenotypic transition from the hyperinflammatory to the hypoinflammatory endotoxin tolerant state, which may last hours, days, or weeks, depending on the strength of the initial TLR response (4,5). The physiologic importance of endotoxin tolerance is still incompletely understood, but likely reflects an attempt to recover homeostasis (3).…”