Western lifestyle linked to maladaptive trained immunity

Immune responses need to be dynamic and capable of adjusting to the context in which immune stimuli are encountered. The cellular responses towards stimuli include classical activation, priming, tolerance, and trained immunity (TI) (Netea and Joosten, 2024). Upon classical activation, the antimicrobial capacity of immune cells is used to resolve an immediate threat. Priming temporarily enhances the cells’ ability to manage future challenges, leading to an additive or synergistic effect upon a secondary challenge, often achieved via the upregulation of surface or intracellular receptors. Tolerance means that a cell becomes less responsive or even unable to respond to a subsequent stimulation. In contrast to the previous three states which describe an immediate or short-term cellular response, TI refers to a state of ‘memory’ that exists after a primary stimulation induces reversible epigenetic and metabolic reprogramming. Once trained, a cell returns to a basal level of functioning (homeostasis), ready to launch an amplified or prolonged inflammatory response upon exposure to a subsequent stimulus (Netea et al., 2016). When cells are exposed to stimuli for a prolonged period, the distinction between priming and training may become blurred. Under these conditions, cells may enter a hybrid state, that is, carrying both traits of TI and traits of prolonged priming. This overlap is particularly difficult to assess when positive feedback loops are involved, such as those driving IL-1β production in autoinflammatory diseases. Careful consideration should be given to the stimulus, its dosing and clearance, as well as the timepoint of assessing the inflammatory response, as each of these may influence the extent to which priming and TI influence the response to a secondary stimulus.

TI allows plants and invertebrate animals to build an immune memory that can be recalled upon subsequent (unrelated) infections or other forms of insults. In contrast, the long-lasting memory of the adaptive immune system is present only in jawed vertebrates, which represent approximately 3% of living species on Earth (Melillo et al., 2018). TI yields an evolutionary advantage by providing non-specific protection against infection, which is particularly beneficial when the host is under threat of multiple pathogens or lacks specific immune memory. The programme of TI remains present even in species that have evolved an adaptive immune system, suggesting an evolutionary pressure that maintains this form of memory, or at least that retaining TI capacity is a tolerable burden. TI can be induced by certain pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns, which can arise both during infection and associated tissue damage, or as a consequence of lifestyle or environmental exposure. Since trainable cells cannot distinguish between a beneficial or a maladaptive training, primary or secondary stimulus and whether its response is beneficial or detrimental to the host, maladaptive TI can occur upon aberrant stimulation (e.g., the consumption of an inflammatory, Western diet), the lack of target specificity (e.g., increased myelopoiesis or inflammatory cytokine production), as well as the failure to timely resolve or limit an immune response. Maladaptive TI contributes to pathological inflammation and/or the development of chronic inflammatory diseases (Fanucchi et al., 2021; Netea et al., 2020; Ochando et al., 2023); such as atherosclerosis (Dong et al., 2024), cardiac dysfunction (Simats et al., 2024), arthritis (Li et al., 2022), and multimorbidity as seen in cardiac dysfunction, as well as skeletal muscle and kidney vulnerability (Nakayama et al., 2024; Ochando et al., 2023). The prevalence of these non-communicable diseases (NCDs) increases with age and concurrently, TI shifts from being solely a protective mechanism to also becoming detrimental to the host. However, the protective effect against infections TI offers in early life enhances an individual’s reproductive fitness. Thus, maladaptive TI fits the concept of antagonistic pleiotropy, where the survival benefits that TI provides in early life outweigh the detrimental effects in later life. In the last century, maladaptive TI has become a more persistent burden on our ageing society. This review aims to place maladaptive TI in the context of NCDs and modern lifestyle, involving industrialisation, pollution, and Western diets. We focus on risk factors for NCDs, which may also be risk factors for maladaptive TI.

In 2012, Kleinnijenhuis et al., 2012 first demonstrated the existence of TI through the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)-dependent non-specific protective effects of the Bacillus Calmette–Guérin vaccine against reinfections. Since then, the list of known TI inducers has grown. The core mechanism of TI is consistent: intracellular signalling cascades, often including the activation of the mTOR–HIF-1α axis, drive metabolic reprogramming and the induction of epigenetic modifications that are sustained even after the initial stimulus is cleared, enabling a rapid and heightened inflammatory response upon a secondary stimulus.

Metabolic reprogramming involves increased oxidative phosphorylation, aerobic glycolysis, TCA cycle, glutaminolysis, and fatty acid metabolism (Ferreira et al., 2024). This ultimately leads to enhanced energy production in the form of adenosine triphosphate and nicotinamide adenine dinucleotide, and the accumulation of signalling metabolites in the cell, for example, fumarate, succinate, and malate, which confer immunometabolic and epigenetic changes (Arts et al., 2016a, Ferreira et al., 2024). For example, glutaminolysis and cholesterol synthesis, in combination with the elevated glycolysis, mediate epigenetic changes via trimethylation of histone H3 at lysine 4 (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac) which change chromatin accessibility of metabolic pathways (Arts et al., 2016b; Xu et al., 2023). The enzyme Set7 catalyses the methylation of H3K4me, leading to transcriptional activation and thus plays an important role in β-glucan-induced TI (Keating et al., 2020; Gates et al., 2024). For a more detailed overview of the metabolic regulation and epigenetic rewiring during TI induction, we refer to recent reviews (Ferreira et al., 2024).

It is important to distinguish between peripheral and central TI. Peripheral TI in mature immune cell populations is typically non-inheritable, important for rapid defence in specific tissues but with a transient impact. However, peripheral TI may also have long-lasting effects in long-lived cell populations with self-renewing capacity, such as alveolar macrophages (Yao et al., 2018) and microglia (Rossi and Lewis, 2018). To date, the phenomenon of peripheral TI inflammatory stimuli has been described in multiple cell types, including monocytes and tissue-resident macrophages (Netea et al., 2016), neutrophils (Moorlag et al., 2020), NK cells (Kleinnijenhuis et al., 2014; Schlums et al., 2015), dendritic cells (Hole et al., 2019), and innate lymphoid cells (Serafini et al., 2022) as well as many non-immune cell types (Hamada et al., 2018).

In contrast to peripheral TI, central TI is typically sustained over longer periods of time (Ochando et al., 2023; Johansson et al., 2023) and is characterised by persistent immunometabolic, epigenetic, and transcriptional changes in haematopoietic stem and progenitor cells (HSPCs) (Mitroulis et al., 2018; Kaufmann et al., 2018; Christ et al., 2018). Central TI is established in the bone marrow, where HSPCs are maintained, self-renew and differentiate, thereby regulating haematopoiesis and egression of cells into the circulation (Morrison and Scadden, 2014; Mendelson and Frenette, 2014). The bone marrow is highly dynamic and adapts to inflammatory stimuli including infections (Burberry et al., 2014; Manz and Boettcher, 2014; Takizawa et al., 2011), ageing (Mitchell et al., 2023; Woods and Guezguez, 2021; Ambrosi et al., 2017), and metabolic imbalances (Ambrosi et al., 2017; Singer et al., 2014). One example of such adaptation is emergency myelopoiesis, which can be triggered by infection, inflammation or myeloablative insult such as chemotherapy (Swann et al., 2024; Chavakis et al., 2019; Manz and Boettcher, 2014). It can also be induced by cytokines, growth factors, or PAMPs (Demel et al., 2022). These stimuli enhance differentiation of myeloid-biased haematopoietic stem cell (HSC) populations and increase proliferation of lineage-committed granulocyte–monocyte progenitors (GMPs).

The long-term effects of central TI on HSCs have been elegantly demonstrated in transplantation studies (Mitroulis et al., 2018). Mice receiving long-term HSCs (LT-HSCs) from β-glucan-trained mice exhibited a higher proportion of myeloid cells and a reduction in B cells. In addition to IL-1β, IFNs, for example, IFNα are also crucial in the induction of TI by β-glucan (Kalafati et al., 2020), and reprogram bone marrow GMPs, resulting in neutrophils with enhanced anti-tumour immunity. In mice, intraperitoneal injection of β-glucan results in the upregulation of IL-1β and GM-CSF, activating the IL-1R1 and GM-CSF receptors, promoting the expansion of myeloid-skewed HSPCs in the bone marrow, including myeloid-biased CD41+ LT-HSCs (Mitroulis et al., 2018), following metabolic rewiring. TI may thus lower the threshold for emergency haematopoiesis.

Beneficial effects of central TI are expected in the context of microbial and viral infections and potentially cancer, as an elevated immune response supports clearance of the pathogen and protection against reinfection or killing of tumour cells, respectively. However, maladaptive central TI may exacerbate inflammatory NCDs.

In chronic inflammatory diseases, a combination of TI, (chronic or) emergency haematopoiesis and priming due to unresolved inflammation may each contribute to the number of innate immune cells and an inflammatory phenotype. Notably, persistent emergency haematopoiesis and central TI have significant mechanistic overlap, yet different outcomes (Swann et al., 2024). For example, inflammatory ligands can drive myeloid-skewed differentiation of HSPCs as part of emergency myelopoiesis, increasing myeloid cell output without necessarily inducing memory-like traits in innate immune cells. Moreover, alterations of the local bone marrow environment may enhance myelopoiesis without conferring immune memory. In contrast, prior LPS exposure can reprogramme HSCs epigenetically, boosting their response to Gram-negative bacteria and improving clearance (de Laval et al., 2020).

While the main focus of the TI field has so far been on the innate immune system, it is increasingly recognised that certain non-immune cell subsets can also undergo long-term epigenetic and functional reprogramming in response to pro-inflammatory cues, termed as ‘pro-inflammatory memory’ (Naik and Fuchs, 2022; Larsen et al., 2021). To date, such memory has been described in various epithelial and non-epithelial cell types, fibroblasts (Cheng et al., 2023) and smooth muscle cells (Villeneuve et al., 2008). Following local inflammation or wounding, this type of memory has been shown to be mostly restricted to or around the primarily affected site (Naik et al., 2017; Levra Levron et al., 2023). In contrast, systemic stimuli, such as infection or metabolic dysregulation, result in training in multiple tissues and organs and can even induce reprogramming in the offspring if encountered during pregnancy (Nash et al., 2023; Lim et al., 2021).

Although beneficial for enhancing tissue repair or resistance to infections, non-immune memory can also have maladaptive consequences. In mouse models, pre-existing inflammatory memory in skin and pancreas (Naik et al., 2017; Falvo et al., 2023) accelerated tissue healing but lowered the threshold for neoplastic transformation and tumour development (Greten and Grivennikov, 2019). Post-inflammatory loss of epithelial diversity and epithelial dysfunction has been observed in the mouse model of acute gastrointestinal graft-versus-host disease, where it manifested as metabolic defects and therefore, reduced regenerative and differentiation capacity of intestinal stem cells (Zhao et al., 2024). Finally, in diabetic mouse models and in vitro hyperglycaemia-exposed endothelial cells, inflammatory reprogramming promoted pro-inflammatory cytokine production, as well as monocyte adhesion and transmigration, contributing to vascular inflammation (Sohrabi et al., 2020; Brasacchio et al., 2009; Villeneuve et al., 2008).

Multiple kinds of TI triggers exist, including lifestyle factors and environmental exposure, as well as several other factors, which are beyond the scope of this review including infections, genetic predisposition, and sterile injury. Many of these triggers are themselves risk factors for chronic inflammatory disease, which exacerbate chronic inflammation and contribute to disease progression by mechanisms including, but not limited to, TI. We will discuss different aspects of a Western lifestyle, including environmental and behavioural factors, that may induce maladaptive TI.

Gout

Gout is characterised by a state of hyperuricaemia followed by the deposition of inflammatory monosodium urate (MSU) crystals in joints, cartilage and connective tissue (ChenXu et al., 2019). Hyperuricaemia may arise from loss-of-function mutations in enzymes involved in purine metabolism or urate transporters. Additionally, risk factors for hyperuricaemia include lifestyle and dietary factors, such as a high purine diet, obesity, and dehydration. Gout flares occur when MSU crystals activate the NLRP3 inflammasome and bioactive IL-1β is released. Urate itself is thought to be a key factor in the persistence and recurrence of inflammation in gout patients, beyond contributing to crystal deposition (Cabău et al., 2020). Indeed, urate stimulation of PBMCs and monocytes ex vivo from gout patients induces a TI phenotype, characterised by a heightened pro-inflammatory cytokine response to secondary stimuli compared to healthy controls. This TI response could be abolished with pharmacological inhibition of histone methylation, highlighting the role of epigenetic modifications, another hallmark of TI, in gout pathology (Crisan et al., 2016; Crisan et al., 2017). Another significant aspect of gout flares is the infiltration of neutrophils into the synovial tissue and fluid, where serine proteases and other pro-inflammatory mediators are released. Neutrophils, despite being short-lived and terminally differentiated cells, have been shown to undergo central TI at the progenitor cell level, resulting in trained neutrophils (Moorlag et al., 2020). Of note, gout flares result from recurrent heightened inflammatory responses that persist long after initial crystal deposition. This hyper-responsiveness alongside epigenetic remodelling is characteristic of TI and not transient or chronic priming.

Taken together, TI in gout may amplify the immune response beyond initial crystal deposition and contributes to the persistence and recurrence of inflammation, exacerbating disease severity. Over successive flares, this heightened inflammatory state of maladaptive TI could lead to an increased risk of chronic arthritis and high incidence of comorbidities, in response to subsequent stimuli. Similarly, TI may increase susceptibility to gout flares resulting in an ongoing inflammatory feedback loop. Yet, further evidence is needed to highlight the role of urate-induced metabolic reprogramming in the context of maladaptive TI (Figure 1).

Figure 1

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Lifestyle changes such as improving dietary habits and physical activity can modulate or even erase pre-existing TI (Table 1). For instance, dietary adjustments, weight management and alcohol moderation benefit gout patients by alleviating symptoms, reducing uric acid and thus the likelihood of crystal formation, preventing TI induction and limiting disease progression (Zhang et al., 2022). Similarly, hypocaloric diets and fasting reduce systemic inflammation in patients with metabolic, autoimmune, and inflammatory diseases (Gopalarathinam et al., 2024; Gasmi et al., 2018). Moreover, Jordan et al., 2019 fasted mice for 19 hours and observed increased activation of the low-energy sensor 5′-AMP-activated protein kinase (AMPK) in hepatocytes and reduced systemic CCL2 production, and reduced mobilisation of monocytes into circulation. Any accompanying weight loss should be maintained to prevent ‘weight cycling’, which has been shown to increase the risk for atherosclerosis in mice due to neutrophil reprogramming in the bone marrow (Lavillegrand et al., 2024). Adipose tissue macrophages of weight-cycled mice showed higher basal levels of TNFα and increased basal and maximal respiration which indicate maladaptive TI (Caslin et al., 2023).

Moderate exercise reduced the inflammatory response after in vitro LPS stimulation of murine BMDMs when compared to inactive mice. These changes were induced by persistent metabolic rewiring and changes to chromatin accessibility that led to an increased expression of anti-inflammatory macrophage-related genes. Additionally, higher mitochondrial quality and higher reliance on mitochondrial OXPHOS, with reduced ROS production, was observed (Murugathasan et al., 2023). The effects of exercise on inflammation and cardiovascular risks have been recently summarised by Zaid et al., 2024. Exercise could be considered a therapeutic approach to either increase the threshold for TI induction or to reverse maladaptive training, but this requires further investigation.

Considering the above-mentioned links between CPS and TI, as well as its additional effect on other parameters, such as dietary choices and physical activity levels, treating and preventing CPS and increasing mental resilience could also be beneficial to prevent maladaptive TI. Among such interventions, one should consider measures that maintain a healthy level of oxytocin. Oxytocin, a key mediator of parturition, lactation, and social behaviour (Froemke and Young, 2021), has recently been linked mechanistically to cardiovascular health. Studies in mice have shown that social isolation reduced plasma levels of oxytocin and worsened atherosclerosis due to changes in hepatic lipid metabolism (Ko et al., 2025). Further, a proteome-wide association study of plasma proteins from the UK Biobank linked five proteins to loneliness and social isolation, which were further related to inflammation and to the development of CVD, depression, and type II diabetes (Shen et al., 2025). Further experiments could tackle the question whether immune cells from socially isolated individuals show a training phenotype. Finally, in our modern age, the growing use of social media and a drop in in-person communication have a high relevance (Schnepf et al., 2024). Structural changes in affected populations should be considered to ameliorate loneliness and increase well-being.

Various reports from the past decade indicate that maladaptive TI can contribute to the onset or exacerbation of chronic inflammatory diseases. Most in vivo mechanistic evidence still comes from mouse models, and most available human data reveal association and not causation (Figure 1).

The prevalence of NCDs, coinciding with increased maladaptive effects of TI, has risen globally over the last few decades during which human-made interventions both increased life expectancy and prolonged exposure to modern lifestyle-associated training stimuli. This is a negligible amount of time in comparison to the evolutionary timeline along which TI has been beneficial. Each individual may have an individual threshold and capacity for TI induction and retention. A clinical test for current training status, as well as trainability compared to baseline, would be a useful diagnostic tool to assess whether maladaptive TI contributes to disease and which patients may benefit from therapeutic intervention. Furthermore, clinical trials that assess lifestyle interventions, for example, Western diet versus fibre-rich diet (Temba et al., 2025) may provide a deeper understanding of maladaptive TI in humans, if TI metrics were assessed.

Despite growing recognition of the role of environmental- and lifestyle-associated influences on TI, the exact influence of many such factors remains largely unresolved. Chronic exposure to pollutants, sensory ecology factors, regional conditions, and endemic microbes may shape the immune system by modulating circadian rhythms, physiological and psychological stress responses, and baseline inflammatory set points. All of these influences may be further modified by cultural factors, including the prevalence of specific hygiene or medical practices, as well as individual- or community-level socio-economic context and associated differences in access to healthcare, education, adequate housing, and clean drinking water. Considering the emerging central role of the microbiome in both innate and adaptive immune regulation in mammals, it will be particularly important to understand how these factors, together with differences between rural and urban lifestyles, shaping the microbiome. Microbiome-dependent pathways may form a key integrative axis linking diverse exposures to trained immune states.

We consider that it is often very difficult to distinguish (chronic) priming from TI in a real-world or clinical setting, in which there is no sterile environment. A clear distinction would require an in-depth integrative analysis of immunological, epigenetic, metabolic, and functional profiling of individuals in a longitudinal fashion. As such, a dataset would need to contain information on a cell (or organism’s state) at (1) baseline, (2) after the primary stimulus, (3) whether it returns to baseline or not, and (4) its state after the secondary stimulus has been resolved.

We conclude that TI once served as an adaptive immune response in innate cells that greatly benefitted a species’ success in pathogen-rich environments. Yet, TI becomes maladaptive in the face of modern lifestyle exposures and an ageing population. TI has indeed become hijacked by poor diet, stress, and pollutants and may now underlie the chronic inflammation driving the current epidemic of NCDs.

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Author details

1. Aurelia Josephine Merbecks

   Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

   Contribution

   Investigation, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner and Eicke Latz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0005-8629-0284

2. Christabel Mennicken

   Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

   Contribution

   Investigation, Writing – original draft, Conceptualization, Writing – review and editing

   Contributed equally with

   Aurelia Josephine Merbecks, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner and Eicke Latz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0009-2967-7975

3. Dennis Marinus de Graaf

   Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

   Contribution

   Conceptualization, Supervision, Investigation, Project administration, Writing – review and editing, Visualization, Writing – original draft

   Contributed equally with

   Aurelia Josephine Merbecks, Christabel Mennicken, Kateryna Shkarina, Theresa Wagner and Eicke Latz

   For correspondence

   Dennis.degraaf@uni-bonn.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9198-7159

4. Kateryna Shkarina

   Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

   Contribution

   Investigation, Writing – original draft

   Contributed equally with

   Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Theresa Wagner and Eicke Latz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2177-4844

5. Theresa Wagner

   Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

   Contribution

   Investigation, Writing – original draft

   Contributed equally with

   Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina and Eicke Latz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0003-6765-5415

6. Eicke Latz

   1. Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany
   2. Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Germany

   Contribution

   Conceptualization, Supervision, Writing – review and editing

   Contributed equally with

   Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina and Theresa Wagner

   For correspondence

   Eicke.Latz@drfz.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1488-5666

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