The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory

Yoshida, Koshi; Maekawa, Tomoko; Zhu, Yujuan; Renard-Guillet, Claire; Chatton, Bruno; Inoue, Kentaro; Uchiyama, Takuro; Ishibashi, Keiichiro; Yamada, Takuji; Ohno, Naohito; Shirahige, Katsuhiko; Okada‐Hatakeyama, Mariko; Ishii, Shunsuke

doi:10.1038/ni.3257

Cited by 156 publications

(167 citation statements)

References 60 publications

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“…Multiple proinflammatory genes were upregulated at the later time point, and this upregulation was accompanied by reduced amounts of epigenetic marks associated with gene silencing and the incomplete recruitment of ATF7, which was associated with the formation of heterochromatin. This study also found that treatment with ␤-glucan induced the phosphorylation of ATF7, a finding analogous to that observed after treatment with LPS (25). Similarly, our study showed the induction of tolerance, most notably, with ␤-glucan and BCG, when cells were only briefly left to rest before rechallenge (24 h), whereas a training effect was seen if cells were left to rest for 3 or 6 days.…”

Section: Figsupporting

confidence: 65%

In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes

Bekkering

Blok

Joosten

et al. 2016

Clin Vaccine Immunol

280

275

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Innate immune memory, or trained immunity, has recently been described to be an important property of cells of the innate immune system. Due to the increased interest in this important new field of immunological investigation, we sought to determine the optimal conditions for an in vitro experimental protocol of monocyte training using three of the most commonly used training stimuli from the literature: ␤-glucan, the bacillus Calmette-Guérin (BCG) vaccine, and oxidized low-density lipoprotein (ox-LDL). We investigated and optimized a protocol of monocyte trained immunity induced by an initial training period with ␤-glucan, BCG, or oxLDL, followed by washing and resting of the cells and, thereafter, restimulation with secondary bacterial stimuli. The training and resting time intervals were varied to identify the optimal setting for the long-term induction of trained immunity. Trained immunity was assessed in terms of the secondary cytokine response, the production of reactive oxygen species, cell morphology, and induction of glycolysis. Monocytes primed with ␤-glucan, BCG, and oxLDL showed increased pro-and antiinflammatory cytokine responses upon restimulation with nonrelated stimuli. Also, all three stimuli induced a switch to glycolysis (the Warburg effect). These effects were most pronounced when the training interval was 24 h and the resting time interval was 6 days. Training with BCG and oxLDL also led to the increased production of reactive oxygen species, whereas training with ␤-glucan led to the decreased production of reactive oxygen species. We describe the optimal conditions for an in vitro experimental model with human primary monocytes for study of the induction of trained innate immunity by microbial and metabolic stimuli.T he immune response is a complex system of cellular and humoral components which have the ability to detect non-selfstructures and confer protection against invading pathogens, playing a crucial role in the survival of multicellular organisms. The immune response has traditionally been divided into the innate immune system and the adaptive immune system. Adaptive immunity, with T and B cells as cellular effectors, develops over several weeks after birth, is highly specific, and builds a specific immunological memory, leading to protection against reinfection. The innate immune system, on the other hand, is classically thought to act rapidly in a nonspecific and identical manner every time that it encounters a pathogen, without having the ability to build an immunological memory.Recently, the concept that innate immunity is nonspecific and completely lacks immunological memory has been challenged. First, pattern recognition receptors (PRRs) confer some specificity to innate immunity, and second, a growing body of literature shows that innate immunity can adapt its function after a first insult (1, 2). Several studies have shown that plants and invertebrates, organisms which lack an adaptive immune system, show enhanced immune responses upon reinfection (3). This phenomenon has r...

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Section: Figsupporting

confidence: 65%

In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes

Bekkering

Blok

Joosten

et al. 2016

Clin Vaccine Immunol

280

275

View full text Add to dashboard Cite

show abstract

“…We propose that, in our model, removal of repressive histone marks is more critical for long-term memory than the addition of active histone marks. In line with our observation, a recent paper studying long-term memory in primary macrophages concluded that removal of repressive H3K9 methylation enabled transcriptional memory induced by LPS exposure (35). In future studies, it will be interesting to survey the nucleosome landscape to query whether nucleosome depletion occurring during Pol II elongation is another event that is inherited, as suggested in recent studies of transcriptional memory in mammalian cells (6,7).…”

Section: Discussionsupporting

confidence: 54%

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Iberg-Badeaux

Collombet

Beaugerie

et al. 2017

Molecular and Cellular Biology

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Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for longterm transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.

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“…Additional studies have shown that the interplay between metabolic pathways, such as glycolysis and glutamine metabolism, is crucial for the induction of the epigenetic and functional changes that take place in monocytes during the induction of trained immunity 61,62 . Furthermore, a recent study showed that both LPS and β-glucan induce trained immunity through a mitogen-activated protein kinasedependent pathway that phosphorylates activating transcription factor 7 (ATF7), subsequently reducing levels of the repressive histone mark 63 . These data suggest that trained immunity is epigenetically and functionally the opposite process to the immune tolerance that is observed in sepsis; this hypothesis has been supported by recent genome-wide assessment of the histone modification landscape induced by either β-glucan (trained immunity) or LPS (immune tolerance) 60 .…”

Section: Reversal Of Immune Suppression In Sepsismentioning

confidence: 99%

The immunopathology of sepsis and potential therapeutic targets

et al. 2017

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Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.

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The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory

Cited by 156 publications

References 60 publications

In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes

In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

The immunopathology of sepsis and potential therapeutic targets

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