Epigenetics and Trained Immunity

Heijden, Charlotte D C C van der; Noz, Marlies P.; Joosten, Leo A. B.; Netea, Mihai G.; Riksen, Niels P.; Keating, Samuel T.

doi:10.1089/ars.2017.7310

Cited by 198 publications

(188 citation statements)

References 154 publications

(227 reference statements)

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“…BCG vaccination for tuberculosis has long been known to confer heterologous crossprotective effects against antigenically unrelated viral and bacterial infections 10,11,60 . This phenomenon has recently been shown to be mediated by an innate immune mechanism called trained immunity in which epigenetic modifications following BCG exposure confer an elevated set-point of transcriptional activation in genes governing pro-inflammatory responses including cytokine genes, immunometabolism and cell polarization 12,[61][62][63][64] . Trained myeloid cells demonstrate elevated responses to subsequent challenge by unrelated antigens or pathogens, and the effect is long-lasting since transcriptional changes are induced by BCG in hematopoietic stem cells and myeloid progenitor cells 11 .…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood. We developed a recombinant BCG (rBCG) that releases the STING agonist, c-di-AMP. Compared with BCG, rBCG demonstrated superior antitumor efficacy in models of NMIBC, more potent pro-inflammatory cytokine responses, greater myeloid cell reprogramming (M1 shift) and enhanced epigenetic and metabolomic changes favoring antitumor immunity. These findings are signatures of trained immunity and reveal that STING pathway activation is a proximal trigger in trained immunity remodeling. Trained immunity may be a central mechanism for both BCG and rBCG antitumor activity in NMIBC. INTRODUCTION:Bacillus Calmette-Guérin (BCG)--the only FDA-approved bacterial agent for cancer immunotherapy--has been in use for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) as a first-line therapy since the late 1970s. More than one-third of patient's with NMIBC will experience tumor recurrence after receiving BCG, and these patients have limited options other than removal of the bladder and creation of a urinary diversion -a major life-altering event. Thus, there is a significant unmet need for improved versions of BCG that provide superior response rates and prevent disease progression 1 . At the current time intravesical options for bladder preserving therapy remain limited.Following bladder instillation, BCG induces a local inflammatory response accompanied by infiltration of granulocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and CD4 + and CD8 + T cells, accompanied by release of pro-inflammatory cytokines including IL-6, TNF-a, and IFN-g 2-7 . However, the specific immune mechanisms leading to BCG-mediated tumor eradication as well as BCG-resistance are not well-understood. BCG has been found to impart potent heterologous protection against non-related viral and bacterial infections; it elicits this protection via an innate immune memory mechanism known as trained immunity 8-11 . Trained immunity is characterized by metabolic, epigenetic and transcriptional reprogramming of both myeloid and lymphoid lineages 12-15 but it has not been extensively studied as an antitumor mechanism during BCG immunotherapy for NMIBC.Recent studies have implicated the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector, stimulator of interferon genes (STING), in a key immune response pathway known as the cytosolic surveillance pathway (CSP), which responds to DNA and cyclic dinucleotides aberrantly present in the cytosol [16][17][18][19] . Activated cGAS catalyzes the formation of 2′3′-cGAMP, a cyclic dinucleotide (CDN) that is a potent STING agonist.Activation of STING leads to stimulation of Type I interferon and NF-κB-mediated immune responses, including elevated dendritic cell priming and T-effector (Teff) cell recruitment 20-23 . 4Small molecule STING agonists elicit potent pro-inflammatory responses, and correspondingly have shown signific...

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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“…While macrophages also efficiently phagocytize Candida, their killing ability is lower than that of neutrophils, leading to the smaller contribution of macrophages during C. albicans infections (Cheng et al, 2012). Moreover, the fungus can induce macrophage cell death by hypha-mediated membrane piercing (Vylkova and Lorenz, 2014;Westman et al, 2018) or activation of NLRP3-dependent pyroptosis (Uwamahoro et al, 2014;Wellington et al, 2014;Vylkova and Lorenz, 2017). The pyroptotic process seems to be independent from candidalysin, although the toxin is responsible for the activation of NLRP3 inflammasome and caspase-1 in macrophages and dendritic cells (Kasper et al, 2018;Rogiers et al, 2019).…”

Section: Anti-candida Innate Immunity At the Mucosamentioning

confidence: 99%

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

Pellón

Nasab

Moyes

2020

Front. Cell. Infect. Microbiol.

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“…The E167K form seems to cause a 40% reduction in cardiovascular events and a 50% reduction in atherosclerotic carotid plaques. [20,184] Moreover, trained immunity, which is orchestrated by epigenetic reprogramming and not associated with any permanent genetic modifications, is a fundamental feature of the immune response in mammals. [180] Further studies are urgently needed since the effect of TM6SF2 variants on the pathogenesis of NAFLD is not yet totally understood.…”

Section: Geneticsmentioning

confidence: 99%

“…Interestingly, individuals with a C allele (167E) have increased risks of dyslipidemia and cardiovascular disease. [184,185] Compared with classical adaptive immune memory, memory within trained immunity is shorter in duration. Other genetic modifiers, such as GCKR and mitochondrial superoxide dismutase 2 (SOD2), have also been reported to influence NAFLD.…”

Section: Geneticsmentioning

confidence: 99%

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease which affects ≈25% of the adult population worldwide, placing a tremendous burden on human health. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, and ultimately, cirrhosis and carcinoma, which are becoming leading reasons for liver transplantation. NAFLD is a complex multifactorial disease involving myriad genetic, metabolic, and environmental factors; it is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. Over the past few decades, countless studies focusing on the investigation of noninvasive diagnosis, pathogenesis, and therapeutics have revealed different aspects of the mechanism and progression of NAFLD. However, effective pharmaceuticals are still in development. Here, the current epidemiology, diagnosis, animal models, pathogenesis, and treatment strategies for NAFLD are comprehensively reviewed, emphasizing the outstanding breakthroughs in the above fields and promising medications in and beyond phase II.

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Epigenetics and Trained Immunity

Abstract: We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders.

Cited by 198 publications

References 154 publications

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

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