In recent years, the concept of trained immunity has been revolutionizing our understanding of how the immune system adapts to threats in a manner previously thought to be exclusive to adaptive immunity. In a groundbreaking new study published in Cell Research in 2025, Schlüter, van Elsas, Priem, and colleagues delve deeply into the phenomenon of trained immunity, elucidating how innate immune cells can develop a form of inflammatory memory that profoundly impacts disease processes. Their findings challenge the classical dichotomy of innate versus adaptive immunity and pave the way for novel therapeutic strategies targeting chronic inflammation and infection.
Trained immunity refers to the enhanced state of responsiveness that innate immune cells acquire after exposure to certain stimuli, such as microbial components or vaccines. Unlike adaptive immunity, which relies on lymphocyte receptors with gene rearrangements, trained immunity operates through epigenetic and metabolic reprogramming of myeloid cells and natural killer (NK) cells. The 2025 study offers fresh insights into how this memory-like response can be initiated and sustained, contributing both to host defense and to pathological inflammation in chronic diseases.
At the heart of this research lies the elucidation of epigenetic modifications—particularly histone modifications and DNA methylation—that underlie the trained immunity phenotype. Upon primary stimulation, innate immune cells undergo specific histone methylation and acetylation changes at promoter and enhancer regions of pro-inflammatory genes. These alterations prime the chromatin landscape, allowing for faster and more robust transcription upon secondary challenge. This epigenetic imprinting is not transient but can persist for weeks or months, maintaining cells in a heightened state of alert even after the initial stimulus subsides.
Moreover, the study emphasizes the crucial role of metabolic rewiring in trained immunity. Innate cells shift their metabolism toward increased glycolysis and glutaminolysis, generating intermediates that serve as substrates or cofactors for chromatin-modifying enzymes. This crosstalk between metabolism and epigenetics reveals a sophisticated regulatory network whereby extracellular signals induce a durable inflammatory memory. Such metabolic remodeling equips the cells with the energy and biosynthetic precursors necessary for a rapid inflammatory response.
Importantly, the authors highlight the dual nature of trained immunity in disease contexts. On one hand, trained immunity enhances resistance to secondary infections by strengthening the innate immune response, offering protection especially in cases where adaptive immunity may be compromised. On the other hand, aberrant or prolonged induction of trained immunity can contribute to chronic inflammatory disorders, such as atherosclerosis, autoimmune diseases, and even neurodegenerative conditions. This dual-edged sword presents both opportunities and challenges for clinical intervention.
The article also delves into the cell types involved in the maintenance of trained immunity. While monocytes and macrophages are the primary players, NK cells and even hematopoietic stem and progenitor cells in the bone marrow have been shown to acquire similar memory-like features. This broad involvement suggests that trained immunity is not merely a peripheral phenomenon but rooted in the central hematopoietic system, with implications for long-term immune modulation.
One of the most captivating revelations from the study is the identification of signaling pathways that trigger trained immunity. Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), detect conserved molecular motifs of pathogens and initiate downstream signaling cascades involving transcription factors like NF-κB and IRF. These pathways activate gene expression programs that remodel chromatin and metabolism, effectively ‘training’ the cell for future encounters. Decoding these molecular machineries opens new avenues for manipulating trained immunity therapeutically.
The therapeutic potential of trained immunity modulation emerges as a centerpiece in this research. Vaccines that induce trained immunity, such as the Bacillus Calmette–Guérin (BCG) vaccine, have demonstrated heterologous protection against unrelated pathogens, underscoring the broad protective effects of this phenomenon. Conversely, dampening aberrant trained immunity responses holds promise for treating chronic inflammatory diseases. The study discusses emerging compounds that target metabolic enzymes, epigenetic writers, and signaling nodes to fine-tune trained immunity intensity and duration.
In addition to in vitro experiments and animal models, the research integrates data from human clinical studies, demonstrating that markers of trained immunity correlate with disease severity and progression in conditions like cardiovascular disease and systemic lupus erythematosus. This translational aspect reinforces the clinical relevance of trained immunity and justifies efforts to develop biomarkers to monitor this state in patients.
The interplay between trained immunity and the microbiome also receives attention in the article. The authors propose that microbial communities residing at mucosal surfaces influence systemic trained immunity by continually providing stimuli that sculpt innate immune memory landscapes. Dysbiosis, or disruption of these microbial communities, may thus predispose individuals to pathological trained immunity and chronic inflammation. This paradigm links environmental factors to immune regulation in a compelling integrative model.
Beyond disease, the article touches upon the evolutionary significance of trained immunity. It suggests that this basal form of immune memory represents a conserved mechanism by which organisms optimize their defense systems in environments teeming with pathogens. Unlike adaptive immunity, which is slower to develop and resource-intensive, trained immunity provides a rapid and cost-efficient response that can be harnessed throughout an organism’s lifetime.
The authors also speculate about the potential role of trained immunity in cancer biology. Trained immune cells might contribute to tumor immune surveillance by sustaining a pro-inflammatory microenvironment hostile to malignant cells. Conversely, chronic activation could exacerbate tumor-promoting inflammation, complicating the relationship between immunity and cancer. This nuanced perspective invites further research into trained immunity’s influence on tumor dynamics.
Crucially, the paper calls for the development of refined experimental models to dissect the temporal dynamics and cellular heterogeneity of trained immunity. Advanced single-cell sequencing techniques and in vivo imaging approaches are deemed essential for unraveling the complexity of innate immune memory in physiological and pathological settings. Such tools will accelerate the identification of precise molecular targets for intervention.
In conclusion, Schlüter and colleagues’ comprehensive study redefines trained immunity as a pivotal determinant of inflammatory memory, with profound implications for health and disease. By bridging epigenetics, metabolism, cellular biology, and clinical science, the research opens fertile ground for translational applications aimed at manipulating immune memory for therapeutic benefit. As we embrace this new frontier, the old axiom that innate immunity lacks memory can finally be laid to rest.
This landmark investigation heralds a paradigm shift in immunology, promising to transform vaccine development, autoimmune disease treatment, and infection control. The intricate choreography of chromatin modifications and metabolic shifts underlying trained immunity reveals a biological sophistication that rivals the adaptive system. Unlocking this potential will no doubt catalyze innovative approaches to harness the power of the immune system in unprecedented ways.
As the field of trained immunity burgeons, future studies are poised to unravel how environmental cues, age, genetics, and lifestyle factors intersect with inflammatory memory to shape disease susceptibility. This knowledge will empower personalized medicine strategies that leverage innate immune training to boost resilience or curb detrimental inflammation. In a world increasingly threatened by emerging infections and chronic conditions, the promise of trained immunity shines brightly as an immunological beacon guiding next-generation healthcare.
Subject of Research: Trained immunity and its role in the induction of inflammatory memory in disease.
Article Title: Trained immunity: induction of an inflammatory memory in disease.
Article References:
Schlüter, T., van Elsas, Y., Priem, B. et al. Trained immunity: induction of an inflammatory memory in disease. Cell Res (2025). https://doi.org/10.1038/s41422-025-01171-y
Image Credits: AI Generated
