Innate immune memory: The evolving role of macrophages in therapy

The concept of immunological memory is well established, describing the phenomenon by which exposure to a pathogen enables the host to develop protective responses against subsequent encounters with the same pathogen —a foundational principle underlying vaccination (Ahmed and Gray, 1996; Plotkin, 2005). Macrophages play a pivotal role in innate immunity, offering the first line of defense against pathogens through rapid, non-specific responses. In 2007, Medzhitov and colleagues demonstrated that toll-like receptor (TLR) genes in murine macrophages bifurcated into two distinct functional categories following in vitro stimulation with lipopolysaccharide (Bukhbinder et al., 2022). These categories, marked by chromatin modifications, either silenced pro-inflammatory mediators or activated antimicrobial effectors, thereby showing adaptive-like properties in macrophages to regulate inflammation (Foster et al., 2007). Shortly after, Netea and colleagues introduced the concept of ‘trained immunity,’ defining it as the memory of the innate immune system, mediated by epigenetic and metabolic reprogramming, leading to enhanced responses upon secondary infections or stimuli (Netea et al., 2016). Since then, trained immunity has been observed in various innate immune cells, including macrophages, monocytes, natural killer (NK), neutrophils, and even hematopoietic stem cells (HSCs) in mouse and human studies (Netea et al., 2011; Saeed et al., 2014). Neutrophils, once thought too short-lived to ‘remember,’ can be centrally trained via reprogrammed granulopoiesis and emerge with enhanced antimicrobial and tissue-protective programs. β-glucan exposure, for example, generates trained neutrophils that promote disease tolerance to influenza and limit immunopathology, highlighting their relevance to barrier-tissue defense and vaccination strategies (Kalafati et al., 2023; Khan et al., 2025). Trained macrophages exhibit heightened functional capacities, including improved pathogen recognition, increased phagocytosis, and more robust cytokine production upon secondary exposure. Notably, ‘phagocytosis’ in the context of trained immunity is cargo-specific: recent work indicates that trained programs can differentially tune macrophage handling of distinct targets, with no change in antibody-dependent cellular phagocytosis (ADCP) but decreased efferocytosis of apoptotic neutrophils—an effect with direct implications for tumor immunity and resolution biology (Chatzis et al., 2025).

Since the formal designation of trained immunity, a series of studies have demonstrated that a primary infection with fungi such as Candida albicans (C.albicans) or an inoculation with a purified compound derived from fungal cell walls called β-glucan could induce long-lasting protection against subsequent heterologous challenges. Although not permanent, this protection resulted from epigenetic modification in monocytes following initial exposure, mediated by intrinsic activation of macrophage and monocyte PI3K/Akt/mTOR pathway (Quintin et al., 2012, Cheng et al., 2014). Findings from β-glucan studies challenged the conventional belief that immunological memory was exclusive to adaptive immunity offering new insights into human immune response to infection, environmental factors and vaccinations. Here, we provide a detailed account of recent advances in trained immunity in monocytes and macrophages, emphasizing developments particularly relevant to the lung.

Therapeutically, trained immunity offers significant potential in enhancing vaccine efficacy and modulating immune responses in disease settings. By harnessing the reprogramming of macrophages, we can improve host defense in the context of infections, as well as explore new avenues in cancer immunotherapy and autoimmune disease management. Central and peripheral training of macrophages, mediated by hematopoietic stem cells (HSCs) or tissue-resident populations, could provide innovative strategies to prevent or treat inflammatory and infectious diseases. This review explores the evolving role of macrophages in innate immune memory and their therapeutic implications in clinical settings.

Trained immunity manifests both in the bone marrow (Sohrabi et al., 2020), where it involves hematopoietic stem and progenitor cells (HSPCs), known as ‘central trained innate memory (CTM),’ and in fully differentiated, mature innate immune cells or tissue-resident cells within peripheral tissues, referred to as ‘peripheral trained innate memory (PTM).’ In this review, we define CTM strictly as training that occurs at the level of HSPCs in the bone marrow, leading to durable imprinting of their myeloid progeny. By contrast, when we discuss macrophages resident within the bone marrow niche (non-HSPC compartment), we consider these as peripheral/local training events occurring in a lymphoid organ or mucosal tissues. A substantial body of evidence supports the concept of CTM, particularly from studies demonstrating trained immunity in HSCs, myeloid progenitors, and BM–derived monocytes following infections or immunization (e.g. with BCG) (Cirovic et al., 2020; Kaufmann et al., 2018; Mitroulis et al., 2018). In contrast, peripheral or local trained immunity, where tissue-resident macrophages undergo long-term functional reprogramming at the site of infection or inflammation remains less well understood (Netea et al., 2020). Therefore, for a comprehensive understanding of trained immunity, parallel investigation is necessary to understand the impact of primary stimuli in the BM as well as peripheral tissues that may collectively contribute to host immune consequences, as shown in an example in Figure 1, where trained immunity is orchestrated in the lungs locally as well as via BM-derived precursors.

Figure 1

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To date, there is limited evidence describing the mechanisms by which tissue-resident macrophages mediate PTM, which is defined as their capacity to confer protection against secondary challenges independently of BM-derived cells. One major barrier to advancing this field is the lack of selective experimental tools and models that can deplete or manipulate specific tissue-resident macrophage populations without affecting other myeloid cells. Traditional approaches, such as clodronate liposome administration to deplete macrophages have many nonspecific effects on other myeloid cells, such as neutrophils (Culemann et al., 2023; Mass, 2023). More recently, transgenic mouse models in which human diphtheria toxin receptor (DTR) is selectively expressed on immune cells (e.g. CD11b-DTR, CD169-DTR, or NAM-DTR) (CD169-cre mice crossed to CX3CR1-flox-DTR) mice have been used to deplete lung interstitial macrophages and broader tissue-resident macrophage populations (Ural et al., 2020; Hua et al., 2018; Yu et al., 2023; Gaertner et al., 2024; Borthwick et al., 2016; Duffield et al., 2005; Miyake et al., 2007). However, even these tools lack the resolution to distinguish among distinct macrophage subsets within tissues, such as in the lung. Nevertheless, recently, several new more sophisticated transgenic mice have been developed that have allowed investigators to probe functions and ontogeny of specific subsets of macrophages. These include CX3CR1-Cre/Ert2-Cre (allows for lineage tracing and targeting of tissue resident macrophages) (Yona et al., 2013), Ms4a3-Cre (allows lineage tracing of bone marrow-derived macrophages in tissues) (Liu et al., 2019) and the split-Cre (Lyve1^ncre:Cx3cr1^ccre; binary transgenic Cre approach to dissect functions of specific subsets of macrophages) (Boura-Halfon et al., 2024). Thus, more precise transcriptomic profiling is needed to identify unique surface markers and regulatory pathways that govern the maintenance and function of resident macrophage subsets (Hua et al., 2018).

To understand the broader implications of trained immunity, it is essential to compare the mechanisms involved in central versus peripheral training, particularly within macrophages across various tissues. While CTM involves systemic changes in HSC-like progenitors leading to enhanced immune responses in peripheral tissues, PTM directly involves epigenetic modifications within tissue-resident macrophages exposed to local pathogens. This distinction is particularly important when analyzing trained immunity across lymphoid and mucosal tissues, as the nature of training in these distinct environments may vary based on local immune challenges and the specific tissue microenvironments involved. An important unresolved question is how turnover dynamics in mucosal macrophage pools influence the relative weight of central vs peripheral training. In tissues like the lung and gut, where resident populations are rapidly replaced by BM-derived precursors, sustained trained immunity likely relies more on central training. For example, the alveolar macrophages (AMs) are known to rapidly undergo cell death following infections and are replaced by bone marrow-derived monocytic precursors (Li et al., 2022b; Aegerter et al., 2020; Hartung and Esser-von Bieren, 2022). However, other lung resident macrophages, such as a subset of interstitial macrophages (IMs) known as the nerve and airway-associated interstitial macrophages (or NAMs) that proliferate after infections may exhibit local training (Ural et al., 2020). Similarly, in organs such as the brain or liver, long-lived resident macrophages may maintain peripheral training for extended periods (Waisman et al., 2015).

The interval between the primary stimulus and detection of trained phenotypes varies with the cellular locus of training and the stimulus used. CTM (HSPC-level) training is typically assessed weeks to months after exposure and can persist long-term because HSPCs continuously generate primed myeloid progeny (e.g. Bacillus Calmette–Guérin (BCG) and β-glucan remodel HSPCs and myeloid progenitors). Peripheral training of mature macrophages is often assayed days to weeks post-exposure and tends to wane with local turnover, especially in mucosal sites. In the lung, influenza and helminth models reveal training detectable weeks later, with durability depending on whether resident pools are replaced by BM-derived cells. Notably, human and animal studies suggest innate memory can persist up to ~1 year in some contexts, consistent with an HSPC reservoir of epigenetically imprinted progenitors (Netea and Joosten, 2024a; Mhlanga et al., 2025).

Frequency of macrophages varies vastly in mucosal tissues such as the gut, skin, and lungs compared to lymphoid tissues, despite a presence of tissue-resident macrophages in all. Macrophages in the lymphoid tissues, such as the spleen and the BM exhibit a wide variety of phenotypes and functions such as removal of apoptotic cells to thereby prevent autoimmunity, as well as kill cancer cells and activating other adaptive as well as innate cells (den Haan and Martinez-Pomares, 2013). Whereas the primary purpose of the mucosal tissues is to serve as a barrier between the body and the external environment, these tissues have profound tissue-specific secondary functions (Dickson et al., 2025). Due to a constant exposure to pathogens, allergens, and environmental pollutants, macrophages in the lungs (AMs), skin (dermal macrophages) as well as the gut (intestinal macrophages) undergo trained immunity for a rapid, localized responses to secondary infections (Li et al., 2022b; Aegerter et al., 2020; Chen et al., 2023b; Feuerstein et al., 2020; Leopold Wager and Schlesinger, 2025; Zahalka et al., 2022; Chen et al., 2022a; Misharin et al., 2017; Wang et al., 2023). Additionally, the plasticity of mucosal macrophages allows them to enhance their immune functions, such as cytokine production and phagocytic activity, in response to repeated exposure to similar pathogens. Moreover, they also exhibit the ability to modulate tissue repair and homeostasis, particularly in the lungs, where macrophages play a crucial role in tissue regeneration after injury caused by pathogens or environmental toxins. In this section, we present a thorough comparative analysis of trained immunity of macrophages in lymphoid vs mucosal tissues. Figure 2 shows a comprehensive and diverse array of stimuli that trigger trained immunity in the myeloid progenitors (Sohrabi et al., 2020) and macrophage populations (BM and periphery) across all tissues that result in host beneficial or host damaging consequences.

Figure 2

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Trained immunity in lymphoid organs critically shapes host defense. When macrophages in the bone marrow, spleen, and lymph nodes acquire a trained phenotype, they respond more rapidly to early danger signals, speeding pathogen clearance and priming adaptive immunity. Yet this heightened reactivity can turn maladaptive, fueling excessive inflammation that underlies autoimmune and other chronic inflammatory conditions. The sections that follow offer an overview of how trained immunity reprograms macrophages in the bone marrow, spleen, and lymph nodes.

Mucosal barriers, including the skin, lungs, and gut are in constant contact with the external environment and thus serve as primary entry points for pathogens and toxins. In this section, we focus on triggers and consequences of trained immunity in mucosal tissues, such as the lungs and gut by highlighting both the resident macrophage and BM-derived precursors that repopulate mucosal tissues as shown in Figure 3.

Figure 3

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Brain

Microglia is the brain’s long-lived resident macrophages are well positioned to develop trained-immunity programs. Repeated systemic LPS exposure results in elevated blood cytokine levels and subsequent morphological changes in the microglia and astrocytes (Wendeln et al., 2018). Additionally, primary hippocampal microglia from S. typhimurium-infected mice show an increase in CD11c and MHCII expression following LPS challenge one month later (Püntener et al., 2012), indicating that microglial priming rather than tolerance contributed to accelerated neurodegeneration, as shown in Alzheimer’s disease (AD). In studies with neonatal mice treated with LPS, increased microglial IL-1β production resulted in decreased neurogenesis in hippocampus resulting in memory impairments (Bilbo et al., 2005; Bland et al., 2010; Lajqi et al., 2020).

Furthermore, activated microglia induce neurotoxic reactive astrocytes via secretion of IL-1α, TNF-α, and C1q (Liddelow et al., 2017). Subsequent TLR engagement drives microglial iron sequestration and triggers AD-like pathology (Zeineh et al., 2015), while anti-C1q antibodies are now being explored clinically to counter this cascade (Lansita et al., 2017). Age-related chronic inflammation exacerbates intracellular iron accumulation, activating the NLRP3 inflammasome and NF-κB pathways that promote neuronal loss (Song and Kim, 2018). The resulting interplay of iron dysregulation, reactive oxygen species, and microglial priming initiates and fuels AD progression, as shown in Figure 4, which is modified from a version adapted from Sfera et al., 2018.

Figure 4

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Recent breakthroughs in medicine and public health have markedly reduced the global toll of infectious and immune-mediated diseases. Nevertheless, stark disparities remain: millions lack reliable access to life-saving therapies, while region-specific threats malaria, tuberculosis, helminth infections, HIV, metabolic disorders, and cancer and the specter of new pandemics continue to exact a heavy price. Because innate immunity governs the earliest phase of host defense, harnessing its memory potential could offer an affordable, broadly protective countermeasure. Long-lived, tissue-resident macrophages exemplify this opportunity; as ‘sentinels, warriors, and healers,’ they patrol virtually every organ and stand ready to mount a rapid, context-appropriate response (Bernier et al., 2025).

Trained immunity in macrophages is a double-edged sword. In acute infections, the heightened antimicrobial functions induced by a prior stimulus such as BCG vaccination can provide non-specific protection against heterologous pathogens, bolstering host defense against Mycobacterium tuberculosis and beyond. Yet in chronic settings like cancer or autoimmune disease, the same amplified responsiveness may become maladaptive, driving persistent inflammation or dampening cytotoxic anti-tumor immunity. Future therapies must, therefore, calibrate this ‘yin and yang,’ amplifying the protective facets of trained immunity while curbing its pathological excesses (Figure 5). In the next sections, we will thoroughly describe how trained immunity can be instrumentalized for host protection in the context of infectious diseases, cancer, neurodegenerative diseases and autoimmunity.

Figure 5

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Trained macrophages can be either allies or adversaries in cancer, depending on their activation state and the tumor microenvironment (Steinbach et al., 2024). As discussed earlier, stimuli such as β-glucan and BCG induce trained immunity that skews macrophages toward a proinflammatory or protective phenotype, thereby boosting tumor surveillance and clearance (Chatzis et al., 2025; Theobald et al., 2024; Buffen et al., 2014; Chen et al., 2023a; van Puffelen et al., 2020). This ‘central’ training begins in BM progenitors and culminates in an inflammatory macrophage program. In an orthotopic model of pancreatic ductal adenocarcinoma, for example, β-glucan traffics to the pancreas and drives a CCR2-dependent influx of trained monocytes and macrophages, enhancing cytotoxic activity and slowing disease progression (Geller et al., 2022). Strategically harnessing such central training to push macrophages whether in the lung, pancreas, or other sites toward a tumoricidal profile could, therefore, improve outcomes in both preclinical studies and cancer patients.

After COVID-19 mRNA vaccination, the ensuing innate activation has been linked both to better responses to immune-checkpoint blockade and, in some settings, to transient systemic inflammation that may accelerate tumor growth (Fendler et al., 2022; Chen et al., 2021). On the other hand, administration of both β-glucan and BCG has recently been shown to induce trained immunity and protect against a subsequent tumor challenge in a mouse model of bladder cancer (Jurado et al., 2025; van Puffelen et al., 2020; Ding et al., 2023; Li et al., 2025) suggesting that β-glucan is a safe and effective adjuvant to enhance BCG immunotherapy in solid tumors. These contrasting outcomes mirror observations with influenza and SARS-CoV-2 vaccines: beyond their antigen-specific protection, each can imprint BM-derived and lung-resident macrophages with BCG-like innate memory, sometimes enhancing host defense, sometimes proving maladaptive in immunocompromised or elderly individuals. Vaccine adjuvants add a further layer, as several have now been shown to epigenetically reprogram macrophages and confer durable resistance to secondary infections (Lee et al., 2022; Wimmers et al., 2021).

Influenza infection in mouse models has been shown to induce trained immunity in AMs to exert long-lasting and tissue-specific antitumor immunity, where trained AMs infiltrate into lung tumor lesions and enhance phagocytic and tumor cell cytotoxic functions via epigenetic and metabolic resistance to the tumor-induced immune suppression. This antitumor ability of AMs is dependent on IFNγ and NK cells (Wang et al., 2023). Conversely, trained tumor-associated macrophages (TAMs) may adopt an immunosuppressive phenotype, supporting tumor growth by promoting angiogenesis, suppressing T-cell responses, and facilitating metastasis through secretion of regulatory cytokines (IL-10, TGF-β) (Kalafati et al., 2020). Epigenetic marks such as increased H3K4me3 in inflammatory gene promoters result in persistent monocyte/macrophage priming, fueling chronic tumor-associated inflammation. Many solid tumors, such as breast, lung, and pancreatic cancers, exploit macrophage training mechanisms to establish an immunosuppressive TME. Repeated exposure to tumor-derived signals, such as metabolic byproducts (lactates from tumor glycolysis), trains macrophages and induce an immunosuppressive phenotype (Biswas and Mantovani, 2010). Subsequently, TAMs suppress cytotoxic T cell responses through the production of Arg1, programmed death-ligand 1 (PD-L1), and IL-10, allowing tumors to evade anti-tumor immunity (Gordon and Martinez, 2010). A recent study described an IL-4 signaling axis in BM-derived from basophils and eosinophils that drive pro-tumorigenic myelopoiesis in non-small cell lung cancer (NSCLC) model causing immunosuppressive myelopoiesis in cancer (LaMarche et al., 2024). Accordingly, pairing immune-checkpoint blockade with therapies that selectively inhibit M2-like, and other regulatory TAM subsets may provide a powerful, synergistic strategy for cancer treatment.

Beyond classical activation, trained programs may rewire macrophage phagocytosis by cargo, a lever with direct relevance in tumors. β-glucan-induced training has been reported to spare ADCP while dampening efferocytosis of apoptotic neutrophils, a combination predicted to (i) preserve antibody-mediated tumor cell clearance yet (ii) limit the accumulation of pro-resolving, immunosuppressive mediators derived from apoptotic-cell uptake within the TME. These cargo-specific effects could be harnessed to tilt TAM function toward antitumor immunity and should be considered when pairing β-glucan/BCG with opsonizing antibodies or checkpoint blockade (Chatzis et al., 2025; Li et al., 2025).

Trained immunity, while advantageous against many infections, can prove harmful in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Unlike systemic macrophage training, which originates in hematopoietic progenitors microglial training unfolds entirely within the brain. The resulting epigenetic imprints persist for years, rendering microglia hyper-responsive and thereby increasing the brain’s vulnerability to chronic inflammation and progressive neurodegeneration (Netea and Joosten, 2024a). Microglial priming is defined as the process of trained immunity in the brain (Haley et al., 2019). In Alzheimer’s disease, trained immunity can worsen pathology. When CD33 on microglia binds sialylated ligands, it recruits the phosphatases SHP-1 and SHP-2, which dampen signaling pathways required for efficient amyloid-β phagocytosis (Griciuc and Tanzi, 2021; McAlpine et al., 2021). Additionally, LPS-stimulated microglia have been shown to cause healthy neuronal death via secretion of TNF, IL-1, and C1q (Sfera et al., 2018). It is now well accepted that epigenetic factors, such as DNA demethylation as well as histone modifications in the promoter region of amyloid precursors cause amyloid beta aggregation in elderly brain causing AD progression (Sanchez-Mut and Gräff, 2015; Liu et al., 2018). In the early stages of AD, increased Ab production and upregulation of inflammatory cytokines have been found to correlate with onset. While in later stages of AD, progression correlates with trained tolerance (Salani et al., 2019; Mishra et al., 2022). Hence, trained immunity of microglia has been correlated with detrimental effects and increased progression of AD. Figure 6 highlights three paradigms in which maladaptive trained immunity fuels neuroinflammation, providing additional evidence that therapeutically targeting macrophage-training pathways could offer neuroprotection in degenerative diseases.

Figure 6

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Additionally, influenza vaccination has also been shown to reduce neuroinflammation in degenerative diseases such as AD. In a large clinical study involving 1,185,611 influenza-vaccinated patients exhibited lower risk of dementia compared to 1,170,868 unvaccinated patients (Bukhbinder et al., 2022). Influenza infection is linked to poorer survival in lung cohorts (Chen et al., 2019; Chen et al., 2022b), highlighting the value of annual influenza vaccination, particularly for patients receiving immune-checkpoint inhibitors to lower risk and improve outcomes (Chong et al., 2020; Failing et al., 2020). These clinical observations echo experimental data showing that a primary influenza infection induces macrophage-mediated trained immunity, which in turn protects against secondary bacterial pneumonia (Aegerter et al., 2020).

Parkinson’s disease (Barriales et al., 2021), an adult-onset neurodegenerative disorder is defined by progressive loss of dopaminergic neurons and the accumulation of α-synuclein–rich Lewy bodies, which drive both its motor and non-motor symptoms (Barriales et al., 2021; Mishra et al., 2022; Dickson, 2025; Schneider et al., 2017). Extracellular α-synuclein is a key driver of Parkinson’s disease that binds TLR1/2 on microglia, activating the TAM-family kinases Mer and (Kim et al., 2013; Fourgeaud et al., 2016; Akalu et al., 2017; Bosurgi et al., 2017). These receptors, which also orchestrate phagocytosis of expendable spinal motor neurons, initiate a pro-phagocytic, inflammatory program that can exacerbate neurodegeneration. Inhibiting Mer/Axl signaling or blocking α-synuclein TLR1/2 engagement may, therefore, attenuate maladaptive microglial training and offer neuroprotective benefit in PD (Hanke and Kielian, 2011).

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disorder that affects the brain and the spinal cord, where the immune system attacks myelin, thus disrupting nerve signals. MS is a lifelong condition with symptoms such as fatigue, numbness, physical imbalance as well as problems with vision, muscles, and cognition (Filippi et al., 2018). Among the triggers for MS, histone modifications such as deacetylation of oligodendrocyte in MS-associated cells (He et al., 2018) as well as histone citrullination in arginine of H3K9me3 preventing secretion of IL-8 and TNF (Fuhrmann and Thompson, 2016) have been hypothesized to lead to chronic MS lesions. However, DNA methylation is critical for brain development and hence, lineagespecific ablation of Dnmt1 in progenitor cells leads to dramatic hypomyelination manifesting in impaired motor coordination (Moyon et al., 2016). Loss of homeostatic microglia (Zrzavy et al., 2017) as well as phenotypic shift to proinflammatory macrophages and their subsequent production of inflammatory cytokines has been linked to progression of MS in both in vivo and in vitro studies (Miron et al., 2013) and slowly expanding lesions in progressive MS (Jäckle et al., 2020).

Controlling maladaptive trained immunity is vital for limiting microglial overactivation and inflammation that drive neurodegenerative diseases. Therapies that selectively dampen this innate memory, whether through cytokine blockade, immune-checkpoint modulation, or targeted small-molecule inhibitors, hold considerable promise. Histone-deacetylase (HDAC) inhibitors are an especially compelling option: by reshaping the microglial epigenome, they can limit amyloid-β and tau accumulation, restore synaptic plasticity, and improve memory in Alzheimer’s disease. Two agents already approved, vorinostat and tucidinostat, act in part by altering microglial acetylation and thus provide practical entry points for translating trained-immunity modulation into neuroprotective therapy (Ding, 2025; Chuang et al., 2009; Wang et al., 2015). Additionally, blocking Axl and Mer kinases on microglia can also be used to target microglial inflammation in neurodegenerative diseases. Selective immune suppression of JAK/STAT pathway via JAK inhibitors may also offer a strategy to attenuate the maladaptive trained immunity in AD and PD (Sunzini et al., 2020). While Duchenne Muscular Dystrophy (DMD) is not a neurodegenerative disease but rather a neuromuscular pathology disorder, dysregulated inflammation via macrophages and monocytes has been linked to its pathology, implicating trained immunity as a maladaptive contributor to disease progression (Chazaud, 2020). DMD is caused by a genetic mutation in the DMD gene on the X-chromosome that encodes dystrophin, which is a membrane-associated cytoskeletal protein (Duan et al., 2021). Mouse models of DMD (mdx mice) have been instrumental in some of the pivotal work that links a nitric oxide synthase transgene in ameliorating the pathology of muscular dystrophy (MD) (Wehling et al., 2001). Mouse experiments have shown that prior to recruitment of monocytes and macrophages to skeletal muscle, they undergo epigenetic modifications in the BM. In vitro stimulation of BMDMs derived from mdx mice induced with MD with TLR agonists show increased expression of both M1 and M2 macrophage markers causing an inappropriate balance between TNF and TGF-β production within the hybrid monocyte/macrophage lineage suggesting evidence of trained immunity causing rapid degeneration (Bhattarai et al., 2022). In conclusion, targeting CTM in DMD might be a viable target in alleviating progression of degenerative pathobiology.

Development of atherosclerosis can also arise as a complication of unresolved autoimmunity in rheumatoid arthritis (RA) patients (Arts et al., 2018; Heinhuis et al., 2011). In RA, synovial macrophages initially exhibit protective roles by producing inflammation-resolving lipid mediators and supporting repair responses in the synovial fibroblasts in vitro (Alivernini et al., 2020). However, persistent activation of macrophages and monocytes contributes to chronic inflammation and tissue damage. These cells are key drivers of cartilage and bone destruction through several mechanisms, including the production of RANKL, upregulation of glycolysis, increased oxygen consumption, and failure to repress pro-inflammatory gene expression due to defective histone methylation at the TNFα and IL6 promoters. Furthermore, hyperactivation of the PI3K/mTOR signaling pathway leads to elevated CD11b expression on CD14⁺ monocytes, which has been associated with reduced responsiveness to anti-rheumatic therapies. These findings underscore the role of trained immunity and epigenetic dysregulation in sustaining pathological inflammation in RA and its cardiovascular comorbidities (Weyand et al., 2017; Arts et al., 2018; Toh et al., 2014; Mulherin et al., 1996; Shirai et al., 2016; Lioté et al., 2003).

Atherosclerotic plaque formation can also emerge from other metabolic diseases such as obesity and diabetes, where macrophages within adipose tissue undergo maladaptive trained immunity, promoting chronic low-grade inflammation through IL-1β and TNF-α production, which contributes to insulin resistance (Hotamisligil and Erbay, 2008). Hyperglycemia and dyslipidemia can induce trained immunity in BM-derived monocytes that infiltrate adipose tissue, where they contribute to insulin resistance (Rohm et al., 2022). Macrophages in adipose tissue of obese hosts undergo metabolic and epigenetic reprogramming, leading to persistent production of IL-1β and TNFα, which disrupt insulin signaling in adipocytes (Hotamisligil and Erbay, 2008). Hence, inflammatory macrophages and monocytes shaped by prior training in the BM can exert detrimental effects across a range of autoimmune and cardiovascular disorders.

Maladaptive trained immunity has emerged as a key contributor to the persistence of chronic inflammation in many other types of autoimmune and immune-mediated inflammatory diseases, such as RA, systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, inflammatory bowel disease (IBD). In these conditions, monocytes and macrophages undergo epigenetic and metabolic rewiring—including H3K4me3 and H3K27ac enrichment at inflammatory loci, shifts toward glycolysis and cholesterol/mevalonate metabolism, and mitochondrial remodeling—that sustain exaggerated IL-1β, TNF, and IL-6 responses long after the initiating trigger has resolved (Ziogas et al., 2023; Municio and Criado, 2020; Riksen et al., 2023). Both CTM, imprinted at the level of hematopoietic stem and progenitor cells, and PTM, occurring in tissue-resident macrophages, contribute to autoimmune pathology. Central reprogramming drives pro-inflammatory myelopoiesis for months, while local training in tissue macrophages supports recurrent inflammation at barrier sites such as the gut, skin, and synovium. Recent work shows that oral barrier inflammation can export pathology to distal sites by training HSPCs through IL-1R–dependent pathways, thereby exacerbating arthritis susceptibility.

Several mechanistic nodes have been identified as actionable targets. The IL-1/NLRP3 axis is a recurrent driver of maladaptive trained immunity, with preclinical and clinical evidence supporting therapeutic blockade using IL-1 antagonists (anakinra, canakinumab) or small-molecule NLRP3 inhibitors (Municio and Criado, 2020; Riksen et al., 2023). Lipid and mevalonate pathway flux also reinforce TI programs in monocytes, suggesting that statins or other metabolic interventions could mitigate disease activity (Riksen et al., 2023). Similarly, glycolytic and mitochondrial pathways (via AKT–mTOR–HIF-1α) sustain hyperinflammatory phenotypes in RA, SLE, and IBD and can be countered by adenosine monophosphate-activated protein kinase (AMPK) activators such as metformin or by mTOR inhibitors such as rapamycin (Municio and Criado, 2020). Epigenetic interventions—including histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors—are being explored to reset chromatin accessibility in chronically trained macrophages, although their clinical utility will depend on achieving specificity while minimizing infection risk (Ziogas et al., 2023).

Disease-focused studies underscore the translational potential of these strategies. In RA and spondyloarthritis, combining cytokine blockade (anti-TNF, anti-IL-1) with metabolic modulators such as metformin has been proposed to dampen flare-associated trained responses (Municio and Criado, 2020). In SLE, interferon-driven myelopoiesis and neutrophil extracellular traps reinforce maladaptive TI, pointing again to the IL-1/NLRP3 axis and metabolic pathways as promising intervention points (Ziogas et al., 2023). In MS, trained microglia and monocytes perpetuate demyelinating inflammation, highlighting opportunities for epigenetic and metabolic reprogramming adjuncts to existing lymphocyte-targeted biologics (Ziogas et al., 2023). Likewise, in psoriasis and IBD, repetitive barrier challenges reprogram tissue macrophages toward persistent IL-1β and TNF-α secretion, suggesting that compartment-specific interventions aimed at local macrophage training may complement systemic therapies (Municio and Criado, 2020). Finally, at the cardiometabolic interface, Western diet, hyperlipidemia, and diabetes drive TI in myeloid cells and exacerbate vascular inflammation; interventions such as statins, IL-1 blockade, and metabolic ‘de-training’ approaches could reduce autoimmune flares in patients with comorbid cardiovascular disease (Riksen et al., 2023; Tercan et al., 2021).

Future therapeutic strategies will need to distinguish central from peripheral training and develop compartment-specific approaches. Nanoparticle delivery systems, bioengineering methods, and tolerogenic cell therapies are being investigated to selectively target HSPCs or tissue macrophages, potentially minimizing systemic immunosuppression while resetting maladaptive innate memory (Municio and Criado, 2020). Equally important will be aligning intervention timing with the biology of TI, as peripheral training is often detectable for days to weeks while central training can persist for months, and implementing biomarkers such as ATAC-seq, metabolomics, and cytokine recall assays to track therapeutic impact (Ziogas et al., 2023; Municio and Criado, 2020; Tercan et al., 2021). Together, these advances clarify that targeting TI in autoimmunity is not vague but rests on well-defined molecular pathways and translational strategies, offering new opportunities to recalibrate innate immune memory for durable disease control. Reversing maladaptive trained immunity in chronic inflammatory and autoimmune diseases will likely demand a multifaceted approach. Promising strategies include metabolic reprogramming, epigenetic modulation with HDAC inhibitors, and biologic therapies that neutralize pivotal pro-inflammatory cytokines such as TNF, IL-17, and IL-1β released by activated macrophages and monocytes.

Advances in modern medicine have sharply reduced deaths and disability from infectious and immune-mediated diseases. Yet deep global inequities in care and new challenges such as emerging pandemics, malaria, tuberculosis, and metabolic disorders continue to strain health-care systems. At the same time, our expanding knowledge of trained immunity reveals a double-edged sword: when properly tuned, it offers broad protection, but when dysregulated, it can drive chronic inflammation. Evidence from animal models and early human studies highlights both the promise and peril of trained macrophages and monocytes, particularly in the respiratory tract. Progress, however, is limited by gaps in experimental tools: we lack models that can selectively ablate specific tissue-resident macrophage subsets, and the cells’ plasticity makes it hard to distinguish ‘central’ (BM-derived) from ‘peripheral’ (local) training. While key epigenetic modifications, including H3K4me3, H3K27ac, H3K9me3, and DNA methylation have been characterized, the exact sequence of epigenomic events driving macrophage reprogramming remains unresolved. Similarly, the role of non-coding RNAs (lncRNAs and miRNAs) in shaping trained immunity is largely unknown. Resolving these issues will be critical for manipulating trained immunity for improved immunotherapy and vaccine design.

The duration of trained immunity also raises important questions. Human studies suggest that innate memory can persist for up to a year, indicating that long-lived hematopoietic stem cells (HSCs) may serve as reservoirs for epigenetically modified myeloid cells. Yet, the interplay between central and peripheral training and the impact of overlapping macrophage markers in tissues such as the lung, skin, and gut remains poorly defined.

Additional uncertainties include whether trained macrophages can revert to a naïve state, and how extrinsic factors like diet, the microbiome, and chronic infections modulate the stability of trained immunity. The heterogeneity among tissue-resident macrophage subsets (e.g. alveolar, interstitial, Kupffer cells, microglia, and splenic macrophages) further complicates our understanding of their distinct capacities for training and systemic influence.

Moreover, the mechanisms governing macrophage metabolic shifts, especially the switch between glycolysis and oxidative phosphorylation, as well as the roles of fatty acid oxidation and glutaminolysis are not fully defined. Given that metabolic modifiers such as mTOR inhibitors and AMPK activators are already used therapeutically, elucidating these pathways could offer new strategies for cancer, infectious, and metabolic diseases.

Lastly, the impact of aging on macrophage-trained immunity is unclear. Age-related changes in metabolism and epigenetics might predispose macrophages to a pro-inflammatory state, reducing their protective capacity. Addressing these gaps is crucial for developing rejuvenation strategies that enhance immune defenses and improve vaccine efficacy and cancer therapies in older populations.

Targeting trained immunity through vaccines and adjuvants is emerging as a powerful strategy to provide broad, non-specific protection against diverse pathogens. Classic examples include BCG and seasonal influenza vaccines, which bolster host defense not only against their intended microbes but also against unrelated infections, underscoring the growing importance of trained immunity in vaccine efficacy. Trained immunity causes outcomes that are context-dependent: while BCG augments resistance to tuberculosis and some cancers, it can worsen malaria pathology. Likewise, COVID-19 vaccines induce durable metabolic and transcriptional reprogramming in monocytes and macrophages, illustrating the wider potential of innate memory but also revealing complexities that certain vaccine-induced trained responses may amplify inflammation or facilitate tumor progression. Fully harnessing the benefits of trained immunity, particularly for immunocompromised or chronically ill individuals, will depend on dissecting the precise molecular and cellular mechanisms that tip the balance between protection and pathology.

1. 1. Aaby P
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