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J Leukoc Biol. Sep 2011; 90(3): 439–446.
PMCID: PMC3157901

Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation


Acute systemic inflammation from infectious and noninfectious etiologies has stereotypic features that progress through an initiation (proinflammatory) phase, an adaptive (anti-inflammatory) phase, and a resolution (restoration of homeostasis) phase. These phase-shifts are accompanied by profound and predictable changes in gene expression and metabolism. Here, we review the emerging concept that the temporal phases of acute systemic inflammation are controlled by an integrated bioenergy and epigenetic bridge that guides the timing of transcriptional and post-transcriptional processes of specific gene sets. This unifying connection depends, at least in part, on redox sensor NAD+-dependent deacetylase, Sirt1, and a NF-κB-dependent p65 and RelB feed-forward and gene-specific pathway that generates silent facultative heterochromatin and active euchromatin. An additional level of regulation for gene-specific reprogramming is generated by differential expression of miRNA that directly and indirectly disrupts translation of inflammatory genes. These molecular reprogramming circuits generate a dynamic chromatin landscape that temporally defines the course of acute inflammation.

Keywords: chromatin remodeling, endotoxin tolerance, facultative heterochromatin, NAD+, Nampt, p65, RelB, sepsis, sirtuin 1, Toll-like receptors


Early historians recognized that inflammation's cardinal signs of rubor (red), calor (hot), tumor (swollen), and dolor (painful) and physiologic changes (functio laesa) have predictable spatial and temporal features [1]. Now, we recognize these elements as interpretations of a common molecular “language,” wherein cells of innate immunity use multiple sensors to recognize and respond to external and internal threats to homeostasis [2, 3]. Although many variations exist among inflammatory diseases, a consistency occurs in local and systemic acute inflammation (e.g., abscess and sepsis) and chronic inflammation (e.g., metabolic syndrome of obesity, atherosclerosis, autoimmunity, and aging). What fundamental processes are responsible for the stereotypic aspects of acute and chronic inflammation?

A rich history generated by many investigators provides a foundation for better understanding the predictable sequence of innate immune responses that support inflammation [2, 46]. Here, we focus on three fundamental cellular processes that coordinate predictable features of acute systemic inflammation: epigenetics, bioenergetics, and miRNA. We include only those events known to directly control epigenetic, bioenergetic, and miRNA reprogramming during innate immune responses of monocytes, macrophages, and neutrophils. Space limitations preclude our discussing epigenetic, bioenergetic, or miRNA reprogramming processes involved in adaptive immunity, myeloid cell development, or chronic inflammation.


No matter what noxious condition incites acute systemic inflammation, the reaction has substantial order and constancy [7, 8]. Its stereotypic features can be divided into phases that generate distinct clinical phenotypes: an initiation (proinflammatory) phase, an adaptive (anti-inflammatory and reparative) phase, and a resolution (restoration of homeostasis) phase [6]; these phases are reflected by changes from hyperinflammation to hypoinflammation to resolution. Although consistent in context, the course of acute systemic inflammation varies from mild and short-lived stages with rapid resolution to severe forms of hyperinflammation, sustained hypoinflammation, and delayed resolution [9]. Hyperinflammation with multiorgan failure, followed by prolonged hypoinflammation, is typical of sepsis, the most common form of severe acute systemic inflammation [7].The risk for developing highly lethal multiorgan failure from acute systemic inflammation is proportional to the “magnitude” of the threat that couples sensing and signaling processes to the proinflammatory “cytokine storm” [8]. This sensing and signaling pathway, albeit complex, virtually always uses TLRs, master regulator NF-κB, and stress kinases to incite transcription of multiple proinflammatory genes (e.g., TNF-α and IL-β), whose products generate the initiating phase [9]. This early phase is rapid and transient, terminating within hours by events that disrupt NF-κB p65 transactivation through post-translational protein deactivation [10], proteosome-dependent degradation [11], and increased mRNA degradation [7], giving way to an adaptive phase typified by the historic phenomenon of endotoxin tolerance [12]. If the adaptive phase is sustained—as it can be for days or weeks following high magnitude stress—outcomes are poor [13, 14]. Resolution heralds restoration of homeostasis.

It was recognized in 1993 that the shift from a proinflammatory to an antiinflammatory endotoxin-tolerant state correlates with “reprogramming” gene expression, a process that represses some genes and activates others [15, 16]. This paradigm of phase-shifts and reprogramming during acute system inflammation is depicted in Fig. 1A. In contrast, Fig. 1B depicts the sustained, proinflammatory pattern of chronic inflammation, which apparently lacks the adaptation or restoration phase of acute inflammation and rarely resolves.

Figure 1.
Phase-shifts during inflammation.


The orderly and stereotypic features of acute systemic inflammation, with the convergence of multiple receptors and signaling pathways on similar transcriptomes, predict reprogramming by epigenetics, the “software” that directs the “hardware” of inflammation's ancient DNA code [17]. Knowledge about the role of epigenetics in inflammation is embryonic compared with cancer and developmental biology [18]. To translate inflammation's encrypted DNA, distinct components of epigenetic processes (transcription factors, histone modifiers, and DNA regulators) must modify highly condensed chromatin that houses the genome, creating a broad landscape of “open” foci (euchromatin) for activating gene expression and “closed” foci (heterochromatin) for silencing gene expression [8]. This plastic landscape must control hundreds to thousands of genes during acute systemic inflammation [19], sequentially directing the basal homeostatic state through the initiation phase, the adaptation phase, and the resolution phase. How does this dynamic and predictable process proceed?

In the basal state of innate immune competency, nucleosomal chromatin at promoters of acute proinflammatory genes is silent but can be rapidly opened following sensing by TLR [20, 21]. For example, TNF-α transcription is restricted by a nucleosome poised over the primary NF-κB site located at its proximal promoter; this nucleosome remodels, as the resident repressor complex is eliminated by TLR-dependent signaling events [22].The chromatin architecture of other rapid-response proinflammatory genes that initiate acute inflammation varies and may or may not require ATP-dependent histone remodeling for activating transcription of promoters that are more difficult to de-repress and require protein synthesis for induction, such as IL-6 [3]. Expression of acute proinflammatory genes can also be limited by blocks at the mRNA elongation stage; such genes constitutively bind transcription factors and cofactors [23]. Despite these variations in activating rapid-response genes, the initiation phase of acute systemic inflammation is similar and virtually always requires the NF-κB signaling pathway to ignite expression of a stereotypic profile of acute proinflammatory genes [24]. Although activated gene sets may vary somewhat based on the specificity of proximal signals, the physiologic outcome is similar: initiation of acute inflammation.

After rapid intiation of the acute systemic inflammatory process, gene-specific epigenetic reprogramming—informed by proximal environmental changes that couple to cell sensing and signaling—shifts the TLR-NF-κB-p65-dependent initiation phase to the adaptation phase, as reviewed in ref. [8]. During this time, the previously poised and then opened promoters of acute proinflammatory genes “close” again by mechanisms that share some, but not all, components of the basal promoter repressor complex [3, 21]. This sequence of de-repression and re-repression of rapid response acute proinflammatory genes develops within 2–6 h of the initial TLR sensing and is critical for cell and host survival [25]. What is happening to switch the initiation phase to the reprogrammed adaptive phase?

A paradox supported that epigenetic-based chromatin shifts in human innate immune leukocytes (macrophages and neutrophils) may control the adaptation phase: animal and human studies of acute systemic inflammation and organ failure correlated with cytosolic NF-κB activation and sustained accumulation of nuclear p65, and this predicted poor outcomes [26]. However, it was known that p65-dependent target genes are repressed within hours after acute systemic inflammation is initiated and remain repressed throughout the adaptive endotoxin-tolerance phase [8, 9]. Thus, the reports of persistent p65 transactivation were counterintuitive. Not understanding this paradox led to implementation of many unsuccessful therapies for acute systemic inflammation, which were based on disrupting NF-κB at some level [25]. To resolve this dilemma, we identified disrupted p65 binding but sustained binding of p50, at the proximal promoter of acute proinflammatory IL-1β and TNF-α during acute systemic inflammation [27, 28]; this pattern occurred despite release of the cytosolic NF-κB p65/p50 complex by activated IκBα, followed by nuclear translocation and accumulation of p65. These results supported previous studies showing the potential importance of DNA-bound p50 homodimers in regulating endotoxin tolerance [29]. Concomitant with disrupted p65 promoter binding was a shift in the epigenetic “histone code” from activated histone H3 serine10 phosphorylation to repressed H3-K9 dimethylation [24]. A surprising discovery was that chromatin remodeling of proinflammatory TNF-α and IL-1β genes in macrophages and neutrophils requires de novo expression of NF-κB member RelB [30]. Newly produced RelB replaces p65 at the proximal promoters of TNF-α and IL-1β, complexes with p50, and directly recruits histone H3-K9 methyltransferase G9a. This leads to assembly of silent, facultative heterochromatin by a large repressor complex containing chromatin modifiers, HP-1, polycomb assembler SUV39H1, H1, HMGB1; and DNA CpG methyltransferases Dnmt3a/b [3133]. This multicomponent, chromatin-determined transcription repressor complex and its histone-remodeling mediators reposition the nucleosome that masks the DNA-binding site for p65 [22]. Importantly, the formation of gene-specific, silent heterochromatin is facultative (i.e., reversible) [31, 3335], as removal of RelB, G9a, HP-1, H1, or HMGB1 by small interfering RNA reverses compacted chromatin and restores p65 responsivity. The restored promoters are again poised, as another TLR signal is required to transfer p65 to DNA and activate transcription [33]. Reversible and loci-specific, facultative heterochromatin also forms at the TNF-α and IL-1β promoters of human sepsis blood leukocytes by a RelB-dependent process [33]. Another important trait of RelB is its dual reprogramming function: it represses transcription at some loci and activates transcription at other loci (e.g., anti-inflammatory IκBα) [36]. Taken together, these data and other reports [3739] indicate that gene-specific epigenetic regulation of the endotoxin-tolerance adaptation phase of acute systemic inflammation requires p65-dependent induction of RelB, which generates a feed-forward process that represses acute proinflammatory genes and activates anti-inflammatory genes [8]. The genome-wide chromatin plasticity generated by RelB is unknown.

Gene-specific epigenetic reprogramming also occurs in endotoxin-tolerant murine macrophages [40], where TLR4-dependent processes remodel chromatin at distinct classes of genes: proinflammatory genes are silenced, and anti-inflammatory and antimicrobial genes are activated. The epigenetic process identified in this study showed that deacetylated histones require ATP-dependent histone remodeling complex Brg1. It was not determined whether RelB contributed to the silencing of endotoxin-tolerant murine macrophages, but our unpublished data indicate participation of RelB in the adaptation phase of acute systemic inflammation in septic mice.

Another study [41] found that murine sepsis epigenetically reprograms lung macrophages during the shift from the initiation-to-adaptive (endotoxin-tolerant) phase and that increased expression of IRAK-M supports this shift by promoting histone deacetylation. RelB was not investigated nor was it determined whether IRAK-M directly modifies chromatin or acts indirectly by disrupting TLR-dependent IRAK1/IRAK4 activation of NF-κB [42]. This group also reported that epigenetic reprogramming supports the IL-4/IL-13-induced shift from classic M1 proinflammatory macrophages to alternative M2 hypoinflammatory macrophages [41]. Another report showed that endotoxin-tolerant murine macrophages develop many characteristics of the IL-4/IL-13 M2 alternative macrophage by a path that requires NF-κB p50 [43]. More studies are needed to establish whether the epigenetic shifts of M1-responsive and M2-adapted macrophages originally connected to adaptive immunity are identical to those generated by innate immunity, TLR-dependent processes.

How do the multiple counter-regulatory, post-transcriptional, and transcription-dependent signals, which disrupt proximal TLR responses, fit the unifying, epigenetic reprogramming paradigm associated with endotoxin tolerance and the adaptation phase of acute systemic inflammation [4446]? Among these counter-regulatory, non-nuclear processes are ubiquitin editing, phosphorylation, and de novo synthesis of negative-feedback mediators (e.g., IRAK-M, A20, mixed function MAPK phosphatase 1, SHIP1). Interestingly, virtually all of these cytosolic or cell membrane repressors influence NF-κB-dependent pathways. Thus, it is possible that they only limit early NF-κB activation and p65-dependent induction of the adaptation phase. Another possibility is that they create alternative adaptive signaling circuits that ultimately converge in the nucleus to support chromatin remodeling. This second explanation is supported by the finding that IRAK-M influences chromatin histone deacetylation and demethylation without known nuclear translocation and promoter binding [47]. This view of reprogrammed cytosolic signaling pathways also is supported by the recent finding that the A20 ubiquitin modifier, which requires protein synthesis, disrupts the IRAK1/IRAK4/TRAF6/TGF-β-activated kinase/IKKγ path without disrupting cytosolic IKKβ, IκBα, and p65 activation [46]. This also could explain how TNF-α and IL-1β promoters are reactivated by p65 when any one of several members of the chromatin repressor complex is removed, and TLR4 is restimulated [22, 25, 28, 33, 34].

How does chromatin remodeling during adaptation affect enhancer regions [21, 48]? This is unknown and important, as nucleosome architecture impacts enhancers and their effect on the magnitude of transcription [49]. Still, another unknown stems from the recent report that IFN-γ treatment can overcome endotoxin tolerance in human blood monocytes by reversing chromatin condensation at the TNF-α and IL-6 promoters. Importantly, this restoration occurs without modifying proximal, counter-regulatory cytosolic pathways [50].

Fig. 2 summarizes the concept of epigenetic chromatin remodeling and gene reprogramming during acute systemic inflammation. The scheme implies a plastic chromatin landscape that temporally controls cell physiology by shifting expression of specific gene sets. The termination of epigenetic reprogramming by unkown mechanisms supports resolution and host survival.

Figure 2.
Epigenetics regulate phase-shifts during acute systemic inflammation.


Profound changes in cellular metabolism parallel gene-specific reprogramming during acute systemic inflammation [51, 52]. A rapid and transient burst of ATP production and increases in NADH through increased glycolysis and mitochondria-dependent oxidative phosphorylation parallel the TLR-dependent initiating phase; ATP levels then quickly fall, and mitochondrial mass decreases [53]. With reductions in generation of NADH and ATP, there are concomitant shifts in ratios of ATP/AMP and NAD+/NADH; this supports the sensing of AMP by AMP-activated kinase and NAD+ by the NAD+-sensing Sirt family [54]. As a result, a reprogramming of metabolic pathways in cytosol and mitochondrial leads to reductions in glycolysis and tricarboxylic acid cycle-induced oxidative phosphorylation, producing a state that simulates cellular ″hibernation″ [55]. This shift of cell redox balance and reprogramming of metabolism parallels development of the adaptive phase of acute systemic inflammation and occurs in macrophages, hepatocytes, and skeletal muscle cells [56, 57]. Epigenetically reprogrammed, endotoxin-tolerant murine bone marrow-derived macrophages modify expression of genes that regulate metabolism [40], suggesting that the epigenome of reprogrammed inflammation can integrate with modifications in metabolism and bioenergetics. In support of this, we found that NAD+-dependent redox sensor Sirt1 coordinates epigenetic phase-shifts during acute systemic inflammation [58]. How does Sirt1 affect the timing of acute systemic inflammation?

Primordial Sir2 of the Sirt family was indentified in yeast as a NAD+-sensing deacetylase that generates heterochromatin [59]. Sirt1 is the human homologue of yeast Sir2; it has diverse functions and molecular links to NF-κB master immunity regulator and chromatin structural modifications [60, 61]. For example, Sirt1 deacetylates and inactivates the transactivation state of p65 [61]; deacetylates specific lysines on histone H3 and H4, H1 nucleosome linker, and histone methyltransferase SUV39H1; and indirectly controls DNA CpG methyltransferase, Dnmt3a/b [62]. These lysine deacetylation “switches” generate facultative heterochromatin [63]. The importance of Sirt1 in repressing transcription is evidenced by its direct deacetylation and inactivation of p300/CREB protein-binding protein acetylation coactivator of transcription, a critical supporter for transcribing acute proinflammatory genes through the NF-κB p65 [64]. Although much is known about Sirt1 deacetylase function in muscle, liver, and pancreatic cells, there are limited data performed in the field of innate immunity and inflammation [65]. Since the Sirts, as major players in cellular homeostasis and human diseases, act through a whole range of biochemical substrates and physiological processes, could they contribute to the timing of inflammation?

As a unifying concept, we hypothesized that NAD+-dependent bioenergetics and epigenetics may combine to influence the chromatin shifts that generate the adaptive phase of endotoxin tolerance during acute systemic inflammation. To test this, we initially used the well-established promonocyte THP-1 cell model of endotoxin tolerance as well as blood leukocytes isolated from humans with acute systemic inflammation [66]. We observed that the NAD+-dependent deacetylase Sirt1 and Nampt-mediated NAD+ biosynthesis combine to control acute systemic inflammation by directing a gene-specific, feed-forward loop that modifies chromatin at specific promoter loci [58]. Several steps participate in this process: 1) Sirt1 directly binds to promoter-bound p65 during the initiation phase of TLR responses and inactivates its transcription function by deacetylating p65 lysine 310; 2) Sirt1 then induces RelB transcription, binds and loads it onto specific promoter loci of acute proinflammatory genes TNF-α and IL-1β, thus recruiting the multicomponent complex that generates loci-specific, facultative heterochromatin; 3) persistent stabilization and enhanced translation of Sirt1 protein—and not transcription—further sustain gene silencing by deacetylating nucleosome histones; 4) a sustained adaptation phase also requires increased expression of Nampt, the rate-limiting enzyme for generating NAD+; 6) surprisingly, Sirt1 and RelB integrate as dual regulators of silent and active chromatin, as Sirt1 promotes transcription of RelB; 7) reductions in Nampt expression and NAD+ production, Sirt1 activation, and promoter binding and RelB expression parallel restoration of immunocompetent euchromatin from facultative heterochromatin.

Thus, NAD+ acts as a driver and the NAD-dependent deacetylase Sirt1, and likely, other members of the Sirt family serve as a universal mediator that coordinates metabolic and inflammatory effects in a tissue-dependent manner in response to changes in NAD+ biosynthesis. Recent data obtained in humans and mice administered endotoxin also support the importance of links between bioenergy and Sirt1 in regulating acute systemic inflammation by reducing hypoxia-inducing factor 1α [67]; these reprogramming effects of Sirt1 modify chromatin in hepatocytes and macrophages.

Fig. 3 conceptualizes how bioenergetics and epigenetics integrate to direct the course of acute systemic inflammation. Readers should refer to Fig. 2 for details of feed-forward, NF-κB-dependent epigenetic modifications that generate silent, facultative heterochromatin and activate euchromatin, thereby directing expression of specific gene sets linked to inflammatory phenotypes.

Figure 3.
TLR sensing and signaling integrate with metabolism, bioenergetics, and epigenetics to guide phase-shifts during acute systemic inflammation.


Another emerging area of gene expression regulation during acute systemic inflammation is ncRNA [68]. Among these ncRNAs are the numerous miRNA of 21- to 23-bp long, which bind to complementary sequences within UTRs of target mRNAs and promote their degradation or more directly arrest translation [69]. Recent data indicate that epigenetic processes control differential expression of miRNA [60] and that specific miRNA support development of hematopoeitic stem cells into competent innate and adaptive immunocytes (reviewed in ref. [70]). miRNA also regulate acute and chronic inflammatory responses (reviewed in ref. [71]). Do miRNA directly or indirectly participate in reprogramming the phase-shifts of acute systemic inflammation?

In our epigenetic studies of phase-shifts, we unexpectedly observed that reversal of the epigenetically silenced transcription restored mRNA levels of TNF-α and IL-1β but not protein production [5]. We reasoned that miRNA might independently regulate gene reprogramming at the post-transcriptional level during acute systemic inflammation and identified differential expression of miR-221, -579, and -125b during the adaptive phase of TLR4 responses in THP-1 cells; we confirmed this observation in blood leukocytes from human and murine acute systemic inflammation [72]. We discovered that translation repression of TNF-α and IL-1β but not IκBα occurred independently of transcription silencing in the TLR-dependent macrophage. We further determined that to limit protein synthesis, miR-221, -579, and -125b interacted with RNA-binding proteins TTP, AUF1, and TIAR at the 3′ UTR of TNF-α mRNA. These interactions were miRNA-specific, as TTP and AUF1 proteins linked to miR-221, whereas TIAR coupled with miR-579 and miR-125b. Functional inhibition of miR-221 prevented TNF-α mRNA degradation, and blocking miR-579, and miR-125b precluded translation arrest. Post-transcriptional silencing was gene-specific, as the miRNA trio did not affect production of this IκBα anti-inflammatory regulator. Thus, distinct regulation of translation by differentially expressed miRNA, perhaps epigenetically reprogrammed, provides assurance in shifting the initiation phase to the adaptation phase. Although this seems like “overkill”, transcription repressor mechanisms reduce mRNA levels by only 60–75% [73].

Fig. 4 is a schematic of direct reprogramming of TNF-α mRNA degradation and translation arrest following differential expression of miRNA during acute systemic inflammation by pattern-dependent recognition of TNF-α 3′ UTR mRNA during TLR4-induced adaptive inflammation. We conclude that TLR4-dependent reprogramming of inflammatory gene transcription and translation is separately regulated during the shift from initiation to adaptation.

Figure 4.
Differential regulation of translation during acute systemic inflammation.

Might miRNA promote shifts between the initiation phase and adaptation phase by indirectly controlling reprogramming? Sustained expression of TLR-dependent miR-146a has been implicated in regulating endotoxin tolerance by directly disrupting translation of TLR signals IRAK1 and TRAF6 [74]. We have confirmed and extended these data by showing that miR-146a modifies signals that assemble a miRNA RISC (in press). Another important miRNA involved in TLR-dependent, miRNA-mediated regulation of inflammation and immune cell differentiation is miR-155, which may provide pro- or anti-inflammatory support depending on the cell type and the signaling pathway involved [75, 76].

Taken together, emerging data support that miRNA regulate phase-shifts during acute systemic inflammation by gene-specific modifications in translation that can be uncoupled from transcription. We speculate that expression of these miRNA, like transcription, is integrated with bioenergetics and epigenetics through TLR- and NF-κB-dependent responses during acute systemic inflammation.


We are just beginning to understand how the interplay of metabolism, bioenergetics, and epigenetics direct feed-forward circuits to modify cellular and organism physiology during inflammation. It is becoming increasingly clear that these coordinated pathways inform the timing of phenotypic shifts during acute systemic inflammation by transcription, translation, and post-translation regulation. Clarifying how these pathways vary between acute and chronic inflammatory reactions, as shown in Fig. 1A and B, is critically important, as the orderly sequence of events associated with acute systemic inflammation is not apparent in chronic inflammatory diseases such as obesity with metabolic syndrome, diabetes, atherosclerosis, aging, and inflammatory dementias.


This research was supported by National Institutes of Health grants R01AI-09169 (C.E.M.), R01AI-065791 (C.E.M.), R01AI-079144 (C.E.M.), MO-1RR 007122 and K08GM086470 to the Wake Forest University General Clinical Research Center. We thank Jean Hu and Sue Cousart for their contributions.


A20 ubiquitin-modifying enzyme
AU-binding factor
DNA methyltransferase
histone linker protein 1
histone H3 lysine 9
high-mobility group box protein 1
heterochromatin protein 1
IL-1R-associated kinase, miR-125b, -579, -221, -146a, and -155=microRNA-125b, -579, -221, -146a, and -155
nicotinamide phosphoryltransferase
noncoding RNA
RNA-induced silencing complex
sirtuin 1
T cell internal antigen-related protein
untranslated region


The authors have no competing interests.


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