Monocyte reprogramming and trained immunity: Linking metabolism to inflammation in non-alcoholic fatty liver disease

Innate immune cells can acquire a form of memory through epigenetic and metabolic reprogramming following exposure to pathogen-associated molecular patterns (PAMPs), resulting in an enhanced, heterologous inflammatory response upon subsequent stimulation, a phenomenon termed trained immunity. This emerging concept challenges the traditional view that immunological memory is restricted to the adaptive immune system and is reshaping current understanding of host defense. Trained immunity is driven by long-lasting functional reprogramming of innate immune cells, particularly monocytes, macrophages, natural killer (NK) cells, dendritic cells, and their progenitors, leading to heightened responsiveness to secondary, often unrelated, stimuli. Comparable forms of innate immune memory have been documented across diverse biological systems, including systemic acquired resistance in plants, immune priming in insects, and trained immunity in mammals, highlighting its evolutionary conservation. The capacity of trained immunity to enhance immune responses provides a mechanistic basis for improved protection against reinfection and strengthened tumor surveillance. However, its dysregulated or excessive activation may also contribute to the development of autoinflammatory and autoimmune diseases, underscoring its dual and context-dependent nature. Consequently, trained immunity holds significant relevance for a wide range of clinical and translational applications, including infectious disease control, cancer immunotherapy, inflammatory disorders, and vaccine development. Harnessing trained immunity in vaccine design offers promising opportunities to achieve broader protective coverage, prolonged immune durability, and improved vaccine efficacy. Despite these advances, key challenges remain, including elucidating the precise molecular mechanisms underlying trained immunity, understanding its crosstalk with adaptive immune responses, and identifying optimal inducers and adjuvants capable of safely modulating trained immune pathways. Addressing these knowledge gaps will be essential for translating the concept of trained immunity into effective and safe therapeutic and vaccine strategies for human health.

Bletilla striata polysaccharide-mediated trained immunity drives the hematopoietic progenitors' expansion and myelopoiesis.

BackgroundTrained immunity, a form of long-term functional reprogramming of innate immune cells through epigenetic and metabolic changes, traditionally confers protection against infections. However, inappropriate activation by endogenous sterile stimuli can drive persistent maladaptive inflammation in non-communicable diseases (NCDs).ObjectiveThis systematic review synthesizes primary evidence for trained immunity in atherosclerosis, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and neurodegenerative disorders, focusing on endogenous inducers, cellular mediators, mechanisms, and translational implications.Data Sources and MethodsFollowing PRISMA guidelines, we included original studies demonstrating trained immunity induced by sterile endogenous signals in the targeted diseases. Narrative synthesis was performed due to heterogeneity precluding meta-analysis.ResultsTwelve primary studies met the inclusion criteria. In atherosclerosis (n = 8 studies), oxLDL, aldosterone, Western diet lipids, and post-myocardial infarction signals induced trained immunity in monocytes or macrophages and hematopoietic progenitors via H3K4me3 enrichment, mTOR/NLRP3 activation, and glycolytic/fatty acid shifts, leading to persistent cytokine hyperproduction (TNF-α, IL-6), foam cell formation, and transmissible plaque progression. In T2DM/hyperglycemia (n = 3), high glucose levels triggered MLL-mediated epigenetic reprogramming and glycolysis-dependent “metabolic memory,” which skewed myelopoiesis and accelerated atherosclerosis despite normoglycemia. In CKD (n = 1), indoxyl sulfate induced AhR-dependent arachidonic acid pathway activation with metabolic rewiring, sustaining systemic inflammation. In neurodegeneration (n = 1), peripheral stimuli caused epigenetic reprogramming in microglia, yielding hyperresponsive or tolerized states modulating amyloid-β pathology. Convergent mechanisms (H3K4me3, glycolysis, mTOR/AhR/NLRP3) highlight trained immunity as a shared driver of chronic sterile inflammation.ConclusionsTrained immunity emerges as a unifying maladaptive mechanism perpetuating low-grade inflammation across these diseases, bridging transient endogenous insults to sustained pathology. Targeting reprogramming pathways, such as glycolysis or epigenetic inhibitors, offers promising therapeutic strategies. Expanded human studies are needed to address preclinical dominance and data gaps, particularly in CKD and neurodegeneration, where evidence is preliminary.

Trained immunity is a functional state of the innate immune response and is characterized by long-term epigenetic reprogramming of innate immune cells. This concept originated in the field of infectious diseases — training of innate immune cells, such as monocytes, macrophages and/or natural killer cells, by infection or vaccination enhances immune responses against microbial pathogens after restimulation. Although initially reported in circulating monocytes and tissue macrophages (termed peripheral trained immunity), subsequent findings indicate that immune progenitor cells in the bone marrow can also be trained (that is, central trained immunity), which explains the long-term innate immunity-mediated protective effects of vaccination against heterologous infections. Although trained immunity is beneficial against infections, its inappropriate induction by endogenous stimuli can also lead to aberrant inflammation. For example, in systemic lupus erythematosus and systemic sclerosis, trained immunity might contribute to inflammatory activity, which promotes disease progression. In organ transplantation, trained immunity has been associated with acute rejection and suppression of trained immunity prolonged allograft survival. This novel concept provides a better understanding of the involvement of the innate immune response in different pathological conditions, and provides a new framework for the development of therapies and treatment strategies that target epigenetic and metabolic pathways of the innate immune system.

Trained immunity is characterized by long-term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular reprogramming leads to increased responsiveness upon restimulation, and is mediated through epigenetic and metabolic modifications. In this review, we describe how molecular mechanisms underlying trained immunity, for example, induced by β-glucan or Bacille Calmette-Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping, and function. We also describe the most commonly used experimental and computational techniques. Finally, we provide a number of examples of how a systems biology approach was applied to study trained immunity to understand interindividual variation or the complex interplay between molecular layers. In conclusion, trained immunity represents an opportunity for regulating innate immune function, and understanding the complex interplay of mechanisms that mediate trained immunity might enable us to employ it as a clinical tool in the future.

Trained Immunity is defined as a biological process normally induced by exogenous or endogenous insults that triggers epigenetic and metabolic reprogramming events associated with long-term adaptation of innate immune cells. This trained phenotype confers enhanced responsiveness to subsequent triggers, resulting in an innate immune “memory” effect. Trained Immunity, in the past decade, has revealed important benefits for host defense and homeostasis, but can also induce potentially harmful outcomes associated with chronic inflammatory disorders or autoimmune diseases. Interestingly, evidence suggest that the “trainers” prompting trained immunity are frequently glycans structures. In fact, the exposure of different types of glycans at the surface of pathogens is a key driver of the training phenotype, leading to the reprogramming of innate immune cells through the recognition of those glycan-triggers by a variety of glycan-binding proteins (GBPs) expressed by the immune cells. β-glucan or mannose-enriched structures in Candida albicans are some of the examples that highlight the potential of glycans in trained immunity, both in homeostasis and in disease. In this review, we will discuss the relevance of glycans exposed by pathogens in establishing key immunological hubs with glycan-recognizing receptors expressed in immune cells, highlighting how this glycan-GBP network can impact trained immunity. Finally, we discuss the power of glycans and GBPs as potential targets in trained immunity, envisioning potential therapeutic applications.

Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette-Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection. HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection. HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens. Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens.

Trained immunity: Target for prophylaxis and therapy

The immune system has traditionally been divided into innate and adaptive branches, with immunological memory considered a hallmark of adaptive immunity. However, recent studies reveal that innate immune cells can also exhibit memory-like properties, known as trained immunity. This phenomenon involves the long-term functional reprogramming of innate immune cells following exposure to exogenous or endogenous stimuli, mediated by epigenetic and metabolic changes. Trained immunity enhances responses to subsequent unrelated challenges and serves as a protective mechanism against reinfection. Nonetheless, it may also contribute to the development of chronic inflammatory diseases such as autoimmune disorders, allergies and atherosclerosis. Whereas much of the research has focused on pathogen-associated molecular patterns as inducers of trained immunity, emerging evidence highlights that sterile inflammation, driven by damage-associated molecular patterns and lifestyle-associated molecular patterns, can similarly induce this immune adaptation. Here we examine the molecular mechanisms underlying damage-associated molecular pattern- and lifestyle-associated molecular pattern-induced trained immunity and their roles in chronic inflammation. This Review also discusses central trained immunity, characterized by the durable reprogramming of hematopoietic stem and progenitor cells, and its implications in disease progression. Finally, potential therapeutic strategies targeting metabolic and epigenetic pathways are considered. Understanding noninfectious stimuli-induced trained immunity offers new insights into chronic inflammatory disease management.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15-20% of patients. This poor response is largely attributed to HCC's immunosuppressive microenvironment, which blunts effective T-cell responses. By illustrating that innate immune cells can acquire memory-like characteristics through a process known as trained immunity, recent evidence has challenged the conventional belief that innate immunity is devoid of memory. This review investigates the potential of trained immunity, which is defined by the long-term functional reprogramming of innate immune cells through epigenetic, transcriptomic, and metabolic changes, to provide new therapeutic opportunities for HCC. We discuss mechanisms by which trained immunity can transform the HCC microenvironment, including enhanced inflammatory cytokine production, repolarization of tumor-associated macrophages toward anti-tumor phenotypes, increased immune cell infiltration, and improved bridging to adaptive immunity. We further evaluate emerging therapeutic strategies leveraging trained immunity principles, including BCG vaccination, β-glucan administration, cytokine-trained NK cell therapy, and innovative combination approaches. Finally, we address potential resistance mechanisms and future directions for clinical application. By integrating trained immunity into conventional immunotherapeutic regimens, we may significantly improve outcomes for HCC patients, potentially transforming advanced disease into a more manageable condition.

Background and Aims Allograft rejection is largely mediated by adaptive immune cells. Although innate immune cells are also involved, their role is less clear. We hypothesize that suppression of innate immune responses, particularly trained innate immunity, can contribute to graft tolerance in transplantation. Trained immunity refers to the long-term epigenetic and metabolic reprogramming of innate immune cells, which potentiates responses to secondary stimuli. Here, we studied the effect of blocking CD40-TRAF6 signaling in myeloid cells on trained immunity induction using in vitro stimulations, ChIP-sequencing and metabolic analyses. We evaluated the effect of myeloid CD40-TRAF6 inhibition on T cell responses in mixed lymphocyte reactions (MLR) and the effect of CD40-TRAF6 inhibitor (TRAF6i) nanobiologic (NB) treatment on allograft rejection in a murine heterotopic heart transplantation model. Method Human peripheral blood mononuclear cells (PBMCs) were stimulated for 24 h with heat-killed Candida albicans (HKCA), a well-described inducer of trained immunity, in presence or absence of TRAF6i, or RPMI medium (control) followed by 5 days of rest. Interleukin-6 (IL-6) and tumor necrosis factor (TNF) production upon restimulation with lipopolysaccharide (LPS) was assessed using ELISA. We performed ChIP-sequencing and metabolic analyses with Seahorse assays at day 6. To investigate the effect of TRAF6i on T cell responses to allogeneic stimuli, we performed 7-day MLR with HKCA- or HKCA+TRAF6i trained monocytes and CellTrace Violet-labeled naïve T cells. Proliferation and FOXP3 expression of naïve T cells was measured by flow cytometry. The effect of TRAF6i-NB on graft survival was assessed by injection of myeloid-directed TRAF6i-NB 0, 2 and 5 days post-transplantation in C57BL/6J mice heterotopically transplanted with BALB/c hearts, that did or did not receive pre-operative CTLA4-Ig treatment. Results TRAF6i treatment inhibited IL-6 and TNF production upon LPS restimulation of HKCA-treated PBMCs in vitro (Fig. 1A). ChIP-sequencing analysis and Seahorse technology respectively revealed that the epigenetic changes (Fig. 1B) and metabolic alterations (Fig. 1C) underlying trained immunity were prevented by TRAF6i. Induction of trained immunity in monocytes reduced differentiation of naïve T cells to FOXP3+CD4+ T cells upon allogeneic stimulation, which was partially reversed by TRAF6i treatment of monocytes (Fig. 1D). Treatment with TRAF6i-NB, combined with CTLA4-Ig, induced >100 days graft survival in 5 out of 6 C57BL/6J mice heterotopically transplanted with BALB/c hearts, while one graft was rejected at 99 days post-transplantation (Fig. 1E). Conclusion Inhibition of TRAF6 prevents trained immunity in monocytes at the functional, epigenetic and metabolic level. We show in vitro that inhibiting trained immunity has the effect of modulating T cell responses to allogeneic stimuli towards FOXP3+CD4+ T cell differentiation. Using a mouse heart transplant model, we show that the combination of TRAF6i and CTLA4-Ig treatment prevents allograft rejection in vivo. This study identifies CD40-TRAF6 signaling as a novel target to inhibit trained immunity and to promote allograft tolerance.

Trained immunity represents a recent concept that elucidates the long-term reprogramming of innate immune cells, enabling them to adapt and respond more effectively to subsequent encounters with diverse pathogens. Initially recognized through the Bacillus Calmette–Guérin vaccine, Candida albicans infection, and β-glucan administration, this phenomenon challenges the traditional view that immune memory is exclusive to the adaptive immune system. Trained immunity is characterized by epigenetic and metabolic modifications in innate immune cells that facilitate enhanced responses to infections through mechanisms like chromatin remodeling and altered gene expression. This review focuses on the implications of trained immunity within the lung environment, which is constantly exposed to a plethora of pathogens and environmental irritants. We discuss the roles of various immune cell types, including alveolar macrophages and dendritic cells, in mediating trained immunity and how these adaptations may influence pulmonary insults and disease. Furthermore, we highlight the potential for leveraging trained immunity to enhance vaccine efficacy and develop novel therapeutic strategies for immune-related lung conditions. As research progresses, understanding trained immunity in the lung could pave the way for innovative interventions that improve lung health and resilience against infections.

Central innate immunity assists time-dependent neurodevelopment by recruiting and interacting with peripheral immune cells. Microglia are the major player of central innate immunity integrating peripheral signals arising from the circumventricular regions lacking the blood-brain barrier (BBB), via neural afferent pathways such as the vagal nerve and also by choroid plexus into the brain ventricles. Defective and/or unrestrained activation of central and peripheral immunity during embryonic development might set an aberrant connectome establishment and brain function, leading to major psychiatric disorders in postnatal stages. Molecular candidates leading to central and peripheral innate immune overactivation identified metabolic substrates and lipid species as major contributors of immunological priming, supporting the role of a metabolic flexibility node during trained immunity. Mechanistically, trained immunity is established by an epigenetic program including DNA methylation and histone acetylation, as the major molecular epigenetic signatures to set immune phenotypes. By definition, immunological training sets reprogramming of innate immune cells, enhancing or repressing immune responses towards a second challenge which potentially might contribute to neurodevelopment disorders. Notably, the innate immune training might be set during pregnancy by maternal immune activation stimuli. In this review, we integrate the most valuable scientific evidence supporting the role of metabolic cues assisting metabolic flexibility, leading to innate immune training during development and its effects on aberrant neurological phenotypes in the offspring. We also add reports supporting the role of methylation and histone acetylation signatures as a major epigenetic mechanism regulating immune training.

Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can also become maladaptive, promoting chronic inflammation, immune dysfunction, and disease. This Review focuses on virus-induced TRIM while also addressing microbial, metabolic, and endogenous inducers. We examine key ligands and receptors that initiate TRIM and dissect the associated signaling and epigenetic pathways. Importantly, we argue that maladaptive TRIM arises not from a specific ligand, receptor, or molecular event, but from contextual factors such as stimulus persistence, dose, tissue microenvironment, and preexisting inflammation. The nature of the secondary challenge also shapes whether a trained response is adaptive or maladaptive. We further discuss TRIM induction in the bone marrow, involvement of both myeloid and nonmyeloid cells, and the role of lipid rafts in sustaining TRIM. We review maladaptive TRIM’s potential contribution to systemic diseases, such as atherosclerosis, diabetes, sepsis, cancer, and autoimmunity, along with its influence on viral vaccine responses. Finally, we outline potential strategies to redirect maladaptive TRIM and propose key outstanding questions for future research.

Beta-glucans enable functional reprogramming of innate immune cells, a process defined as “trained immunity”, which results in enhanced host responsiveness against primary (training) and/or secondary infections (resilience). Trained immunity holds great promise for promoting immune responses in groups that are at risk (e.g. elderly and patients). In this study, we modified an existing in vitro model for trained immunity by actively inducing monocyte-to-macrophage differentiation using M-CSF and applying continuous exposure. This model reflects mucosal exposure to β-glucans and was used to study the training effects of a variety of soluble or non-soluble β-glucans derived from different sources including oat, mushrooms and yeast. In addition, trained immunity effects were related to pattern recognition receptor usage, to which end, we analyzed β-glucan-mediated Dectin-1 activation. We demonstrated that β-glucans, with different sources and solubilities, induced training and/or resilience effects. Notably, trained immunity significantly correlated with Dectin-1 receptor activation, yet Dectin-1 receptor activation did not perform as a sole predictor for β-glucan-mediated trained immunity. The model, as validated in this study, adds on to the existing in vitro model by specifically investigating macrophage responses and can be applied to select non-digestible dietary polysaccharides and other components for their potential to induce trained immunity.