During the last few years, a growing body of evidence has shown that immunological memory is not an exclusive trait of lymphocytes, as many inflammatory insults can alter the functionality and the ...responsiveness of the innate immune system in the long term. Innate immune cells, such as monocytes, macrophages, dendritic cells, and NK cells can be influenced by the encounters with inflammatory stimuli, undergoing functional reprogramming and developing changed responses to subsequent chellenges. The long‐term reprogramming depends on the rewiring of cell metabolism and epigenetic processes, and they stay at the basis of induction of both innate immune memory (also termed trained immunity) and innate immune tolerance. Here, we review the central role that the effects of this long‐term reprogramming of innate immune cells plays in a number of clinically relevant conditions such as vaccination, atherosclerosis, sepsis, and cancer.
In this Review, we will focus on the metabolic and epigenetic changes that take place during trained immunity and tolerance and the most relevant clinical conditions.
Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its ...previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.
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•Set7 regulates enhanced cytokine production in trained immunity in vitro•Set7 knockout mice are unable to mount trained immunity against endotoxin challenge•Set7 modulates cellular respiration in β-glucan-trained macrophages•Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells
Using a combination of pharmacological and genetic approaches, Keating et al. show that the Set7 methyltransferase is a regulator of trained immunity induced by β-glucan. Activation of Set7 increases oxidative phosphorylation in trained cells via histone lysine methylation at gene enhancers of key enzymes of the TCA cycle.
Abstract
People with advanced age have a higher susceptibility to infections and exhibit increased mortality and morbidity as the ability of the immune system to combat infections decreases with age. ...While innate immune cells display functional defects such as decreased phagocytosis, chemotaxis and cytokine production, adaptive immune cells exhibit reduced receptor diversity, defective antibody production and a sharp decline in naive cell populations. Successful responses to vaccination in the elderly are critical to prevent common infections such as influenza and pneumonia, but vaccine efficacy decreases in older individuals compared with young adults. Trained immunity is a newly emerging concept that showed that innate immune cells possess non-specific immunological memory established through epigenetic and metabolic reprogramming upon encountering certain pathogenic stimuli. Clinical studies suggest that trained immunity can be utilized to enhance immune responses against infections and improve the efficiency of vaccinations in adults; however, how trained immunity responses are shaped with advanced age is still an open question. In this review, we provide an overview of the age-related changes in the immune system with a focus on innate immunity, discuss current vaccination strategies for the elderly, present the concept of trained immunity and propose it as a novel approach to enhance responses against infections and vaccinations in the elderly population.
How ‘trained immunity’ enhances immune responses
Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using ...complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency ...and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
Synopsis
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
Deletion of p38γ/p38δ protects mice from C. albicans infection.
p38γ/p38δ control fungicidal capacity through ROS and iNOS production.
p38γ/p38δ regulate the inflammatory response to C. albicans through a new Dectin‐1 pathway in macrophages.
Chemical inhibition of p38γ/p38δ reduces fungal burden in a candidiasis mouse model.
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is ...characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
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•IL-37 counteracts the protective effects of trained immunity (TI) in vivo•IL-37 suppresses pro-inflammatory cytokine production•IL-37 reverses immunometabolic changes and histone modifications characteristic of TI
Cavalli et al. demonstrate that the anti-inflammatory cytokine IL-37 regulates trained immunity (TI) in vivo. IL-37 reverses the immunometabolic changes and histone post-translational modifications underlying TI, thereby suppressing pro-inflammatory cytokine production. This regulatory role of IL-37 over myeloid-driven inflammation has implications for immune-mediated disorders and for host responses against pathogens.
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and ...individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed “trained immunity,” by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Netea and colleagues argue that we may be able to prevent or decrease the severity of SARS-CoV-2 infection through certain clinically approved live vaccines that “train” the innate immune system to be broadly vigilant against viral infection.
Trained immunity refers to the long-lasting memory traits of innate immunity. Recent studies have shown that trained immunity is orchestrated by sustained changes in epigenetic marks and metabolic ...pathways, leading to an altered transcriptional response to a second challenge. However, the potential heterogeneity of trained-immunity induction in innate immune cells has not been explored. In this study, we demonstrate cellular transcriptional programs in response to 4 different inducers of trained immunity in monocyte populations at single-cell resolution. Specifically, we identified 3 monocyte subpopulations upon the induction of trained immunity, and replicated these findings in an in vivo study. In addition, we found gene signatures consistent with these functional programs in patients with ulcerative colitis, sepsis, and COVID-19, suggesting the impact of trained-immunity programs in immune-mediated diseases.
Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We ...show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.
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•Dimethyl itaconate induces trained immunity in human monocytes•Dimethyl itaconate-induced trained immunity is mediated through glutathione synthesis•Dimethyl itaconate protects mice against infection•Basal plasma itaconate associates with increased human BCG trained immunity capacity
Itaconate has broad immunomodulatory properties in mammalian systems and presents various anti-inflammatory properties. Ferreira et al. demonstrate that a derivative of itaconate, dimethyl itaconate, induces trained immunity, thus highlighting the dual role of dimethyl itaconate as a molecule with anti-inflammatory and immune potentiating characteristics.
The last few years have witnessed an increasing body of evidence that challenges the traditional view that immunological memory is an exclusive trait of the adaptive immune system. Myeloid cells can ...show increased responsiveness upon subsequent stimulation with the same or a different stimulus, well after the initial challenge. This de facto innate immune memory has been termed “trained immunity” and is involved in infections, vaccination and inflammatory diseases. Trained immunity is based on two main pillars: the epigenetic and metabolic reprogramming of cells. In this review we discuss the latest insights into the epigenetic mechanisms behind the induction of trained immunity, as well as the role of different cellular metabolites and metabolic networks in the induction, regulation and maintenance of trained immunity.
Recent advances in the field of innate immunity have revealed the mechanisms of trained immunity (innate immune memory): namely the epigenetic and metabolic reprogramming of cells. Fanucchi et al. review these advances with deeper insight into the roles of noncoding RNA and genome architecture in the “writing” of trained immunity.
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