Abstract:Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, … Show more
“…Differential accessibility analysis, based on MACS2-defined peak regions for GMPs and neutrophils from β-glucan-treated mice compared with the respective cells from control-treated mice, revealed differentially accessible regions (DARs) in GMPs and neutrophils upon induction of trained immunity ( Figure 5 E). The top 10 significantly enriched GO terms in GMPs and neutrophils, identified on the basis of genes annotated to regions more accessible due to β-glucan-induced training, not only revealed terms such as “regulation of myeloid cell differentiation,” but also cell metabolism-related terms ( Figure 5 E), consistent with the findings of the RNA sequencing results from TANs ( Figure 2 C) and with the previously described involvement of immunometabolic pathways in the induction of trained immunity ( Arts et al., 2016 ; Ieronymaki et al., 2019 ). Figure 5 Epigenetic Rewiring of Trained Granulopoiesis Splenic neutrophils and BM GMPs were sorted from mice that were treated with β-glucan or with PBS 7 days earlier and scATACseq was performed.…”
Summary
Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.
“…Differential accessibility analysis, based on MACS2-defined peak regions for GMPs and neutrophils from β-glucan-treated mice compared with the respective cells from control-treated mice, revealed differentially accessible regions (DARs) in GMPs and neutrophils upon induction of trained immunity ( Figure 5 E). The top 10 significantly enriched GO terms in GMPs and neutrophils, identified on the basis of genes annotated to regions more accessible due to β-glucan-induced training, not only revealed terms such as “regulation of myeloid cell differentiation,” but also cell metabolism-related terms ( Figure 5 E), consistent with the findings of the RNA sequencing results from TANs ( Figure 2 C) and with the previously described involvement of immunometabolic pathways in the induction of trained immunity ( Arts et al., 2016 ; Ieronymaki et al., 2019 ). Figure 5 Epigenetic Rewiring of Trained Granulopoiesis Splenic neutrophils and BM GMPs were sorted from mice that were treated with β-glucan or with PBS 7 days earlier and scATACseq was performed.…”
Summary
Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.
“…These effects of insulin are mediated by its signal transduction pathway involving the insulin receptor and insulin like growth factor 1 receptor on the cell membrane [46]. Binding of insulin on the insulin receptor or insulin like growth factor 1 receptor (IGF1R) results in the phosphorylation of insulin receptor substrate 1/2 (IRS1/2) at its tyrosine residues, which results in the subsequent activation of two main pathways, the phosphoinositide3-kinase(PI3K)/protein kinase B (AKT) pathway and the mitogen-activated protein kinase (MAPK) pathway [46,47].…”
Section: Insulin Signaling and Insulin Resistancementioning
Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxidative stress, and responds by increasing antioxidant transcription levels. Therefore, Nrf2 has emerged as a critical new target for combating insulin resistance and subsequently, obesity. However, the effects of Nrf2 on insulin resistance and obesity are controversial. This review focuses on the current state of research on the interplay of inflammation and oxidative stress in obesity, the role of the Nrf2 pathway in obesity and insulin resistance, and the potential use of Nrf2 activators for the treatment of insulin resistance.
“…Organisms lacking adaptive immunity were shown to have enhanced resistance to subsequent infections (trained immunity). Innate trained immunity occurs in human monocytes and MØ; mTOR/Akt/PI3K‐regulated metabolic reprogramming, including increased glutamine metabolism, a shift from OXPHOS‐to‐aerobic glycolysis, and cholesterol synthesis contribute to this process 10‐104 . However, IAV also alters these pathways, and one study found trained immunity had no effect on IAV infection 15 …”
Section: The Immune Response To Influenza Infectionmentioning
The metabolic impact of influenza A virus (IAV) infections on immune cells remains largely uncharacterized. However, much is known about the metabolism of IAV infection and immunometabolism. Thus, we will consider four main factors: the metabolic requirements of influenza virus, metabolic reprogramming of immune cells that are mobilized to fight IAV infection, the impact of systemic or local metabolism on the infection and immune response, and vice versa. We will also address the interplay of metabolism and cytokines with a focus on those relevant to IAV infections. Finally, we will limit information on immunometabolism to key cell types critical to fighting IAV infection. We will relate this information to the unique metabolic demands on immune cells and discuss how their translocation through nutrient diverse and changing environments may affect their functions in IAV infection.
| ME TABOLIS M AND THE LUNG MICROENVIRONMENT
| Steady-state metabolismUnder aerobic conditions, cells sustain themselves catabolically using glycolytic carbons to fuel the tricarboxylic acid (TCA) cycle.
AbstractRecent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenzainduced changes in metabolic homeostasis on disease progression.
K E Y W O R D Shost pathogen, immune response, Immunometabolism, Influenza, metabolism, viral infection, virus | 141 BAHADORAN et Al.
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