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

Abstract

Gene-selective epigenetic reprogramming and shifts in cellular bioenergetics develop when Toll-like receptors (TLR) recognize and respond to systemic life-threatening infections. Using a human monocyte cell model of endotoxin tolerance and human leukocytes from acute systemic inflammation with sepsis, we report that energy sensor sirtuin 1 (SIRT1) coordinates the epigenetic and bioenergy shifts. After TLR4 signaling, SIRT1 rapidly accumulated at the promoters of TNF-␣ and IL-1␤, but not IB␣; SIRT1 promoter binding was dependent on its co-factor, NAD ؉ . During this initial process, SIRT1 deacetylated RelA/ p65 lysine 310 and nucleosomal histone H4 lysine 16 to promote termination of NFB-dependent transcription. SIRT1 then remained promoter bound and recruited de novo induced RelB, which directed assembly of the mature transcription repressor complex that generates endotoxin tolerance. SIRT1 also promoted de novo expression of RelB. During sustained endotoxin tolerance, nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for endogenous production of NAD ؉ , and SIRT1 expression increased. The elevation of SIRT1 required protein stabilization and enhanced translation. To support the coordination of bioenergetics in human sepsis, we observed elevated NAD ؉ levels concomitant with SIRT1 and RelB accumulation at the TNF-␣ promoter of endotoxin tolerant sepsis blood leukocytes. We conclude that TLR4 stimulation and human sepsis activate pathways that couple NAD ؉ and its sensor SIRT1 with epigenetic reprogramming.Two cellular processes predictably accompany TLR-mediated acute systemic inflammation caused by sepsis, a highly destructive and often lethal process. 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).Others and we (6 -9) reported how temporal transitions in epigenetic programming alter the course of acute inflammation. NFB master ...

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

“…Yeung et al demonstrated that SIRT1-mediated deacetylation of Lys310 inhibits the transactivation of the RelA/p65 subunit and consequently suppresses NF-κB-dependent gene expression [39]. Liu et al reported that chronic inflammation stimulates the accumulation of SIRT1 in the promoter regions of cytokine genes and then induces deacetylation at the RelA/p65 subunit of the NF-κB complex [44]. Moreover, SIRT1-mediated deacetylation of NF-κB is crucially involved in the resolution of inflammation and metabolic disorders [45][46][47].…”

Sequential Actions of SIRT1-RELB-SIRT3 Coordinate Nuclear-Mitochondrial Communication during Immunometabolic Adaptation to Acute Inflammation and Sepsis

“…Real-time PCR-mRNA levels of human SIRT1, RELB, SIRT3 and murine Sirt1, Relb, Sirt3, and mitochondrial genes were measured by quantitative RT-PCR using gene-specific TaqMan primer/probe sets in an ABI prism 7000 sequence detection system (Applied Biosystems) as described (15). GAPDH mRNA was the internal loading control.…”

“…Nuclear SIRT1 and SIRT6 play a critical role in switching the initial inflammatory response to adaptation. In monocytes and neutrophils, this switch generates silent heterochromatin by inactivating NFB factor RelA/ p65 and activating NFB RELB transcription factor and other histone and DNA modifiers (2,(13)(14)(15)(16). Mechanistically, SIRT1 deacetylates lysine 310 of RelA/p65 and histone protein H1K27 and recruits RELB to promoters of target genes (15).…”

“…In monocytes and neutrophils, this switch generates silent heterochromatin by inactivating NFB factor RelA/ p65 and activating NFB RELB transcription factor and other histone and DNA modifiers (2,(13)(14)(15)(16). Mechanistically, SIRT1 deacetylates lysine 310 of RelA/p65 and histone protein H1K27 and recruits RELB to promoters of target genes (15). SIRT6 also deacetylates RelA/p65 and histone H3K9 (17,18) to exert antiproinflammatory activity.…”

“…Increases in NAD ϩ availability and the cooperative actions of nuclear SIRT1, SIRT6, and RELB are required to move from initiation to adaptation (15,19). When NAD ϩ or SIRT1 levels decrease in cell models of sepsis and sepsis mice, the initial acute inflammatory response is amplified by allowing excessive NFB RelA/p65 activation (19,20).…”