Lactate: The Unexpected Molecular Trainer of Innate Immunity
In the rapidly evolving landscape of immunology, a groundbreaking discovery is reshaping our understanding of how the innate immune system adapts and remembers past microbial encounters. While adaptive immunity’s memory has long been a cornerstone of vaccine effectiveness, the innate immune system—traditionally viewed as a blunt and immediate defense mechanism—has revealed a remarkable ability to “train” itself. This phenomenon, aptly named trained immunity, is now linked to the metabolic byproduct lactate, a molecule once dismissed as mere metabolic waste but now emerging as a key regulator of immune memory at the molecular level.
Historically, the immune system’s defenses have been categorized into two distinct arms: innate immunity, the body’s first line of defense from birth against a broad range of bacteria and viruses, and adaptive immunity, which tailors long-term defense through specific recognition and memory formation against particular pathogens. Vaccines have conventionally targeted adaptive immunity, instructing lymphocytes to recognize and neutralize invading organisms. Yet, an intriguing exception has been the Bacillus Calmette-Guérin (BCG) vaccine, primarily designed against tuberculosis, which goes beyond stimulating adaptive responses. BCG notably enhances innate immune vigilance, broadly reducing infections from various respiratory pathogens by effectively “training” innate immune cells.
This trained immunity has puzzled scientists for years. How does a vaccine targeting a single bacterium enhance the broader responsiveness of innate immune cells to multiple unrelated pathogens? The answer lies at the intersection of cellular metabolism and epigenetics, the latter referring to the molecular modifications that regulate gene expression without altering the underlying DNA sequence. Recently, an international team led by Mihai Netea at Radboud University Medical Center has elucidated this mechanism with unprecedented depth, revealing how metabolic shifts engender lasting epigenetic changes that underpin trained immunity.
Central to their discovery is lactate, a molecule produced abundantly during heightened glycolytic activity when immune cells ramp up glucose consumption. While lactate had long been relegated to the status of a metabolic byproduct accumulating during anaerobic respiration, emerging evidence indicates it plays a far more sophisticated role. Specifically, lactate can modify histones, the protein complexes around which DNA is wound, through a process called histone lactylation. This epigenetic modification alters chromatin structure, modulating gene accessibility and expression, essentially reprogramming immune cells to a more alert and reactive state.
Using sophisticated molecular assays and immune profiling of BCG-vaccinated healthy volunteers, the researchers observed strong correlations between lactate levels and the production of inflammatory cytokines, signaling molecules that orchestrate immune defense. These findings revealed that lactate-induced histone lactylation persisted in innate immune cells for up to three months post-vaccination, sustaining an enhanced inflammatory response poised to counter new microbial threats. Moreover, pharmacologically disrupting lactate production significantly diminished the trained immunity response, underscoring lactate’s pivotal role as a molecular regulator rather than an inert byproduct.
The implications of these findings resonate beyond the immediate scope of tuberculosis or BCG vaccination. They challenge the dogma of the immune system’s division into rigidly separate innate and adaptive arms, highlighting a nuanced metabolic-epigenetic crosstalk that enables innate immune cells to retain functional memory. This metabolic rewiring encompasses not only enhanced glycolysis and lactate production but also a cascade of epigenetic alterations that recalibrate gene expression landscapes, enabling innate cells to respond more vigorously upon subsequent encounters with diverse pathogens.
Technically, histone lactylation represents a novel layer of epigenetic modification, distinct yet analogous to more classical marks like methylation and acetylation. It involves the covalent attachment of lactyl groups to lysine residues on histones, modulating chromatin configuration and gene transcription patterns. In the context of trained immunity, this process facilitates the upregulation of key inflammatory genes, effectively “bookmarking” regions of the genome for rapid activation. The persistence of these modifications implies that metabolic states can exert long-term influence over immune cell behavior, a concept with profound therapeutic potential.
The research employed cutting-edge technologies including chromatin immunoprecipitation sequencing (ChIP-seq) to map lactylation sites genome-wide and advanced mass spectrometry for precise quantification. These approaches combined to provide a holistic view of how metabolic shifts translate into epigenetic remodeling in human immune cells. Their experimental design included controlled human vaccination trials paired with in vitro manipulation of metabolic pathways, allowing the team to causally link lactate production with trained immunity outcomes.
This metabolic-epigenetic interplay not only sheds light on the mechanisms induced by the BCG vaccine but also opens avenues to enhance vaccine efficacy and design novel immunomodulatory therapies. If lactate can be harnessed or mimicked pharmacologically, it may be possible to fine-tune innate immune responses, offering broad protection against respiratory infections and possibly even cancer and autoimmune diseases where innate immunity plays a critical role.
Importantly, the study highlights the plasticity of the innate immune system and its capacity for durable memory-like properties traditionally ascribed only to adaptive immunity. This paradigm shift deepens our understanding of host defense and emphasizes metabolism as a therapeutic target to modulate immunity. The interplay between sugars, lactate, and epigenetic memory represents a frontier of immunology that marries bioenergetics with genomics, promising a new era of metabolic immunotherapy.
Additionally, the discovery reframes lactate, the long-maligned molecule associated with muscle fatigue and metabolic stress, as an essential signaling mediator finely tuning immune readiness. This redefinition inspires reconsideration of metabolic byproducts in biological regulation and their potential as biomarkers or intervention points in immune-related diseases.
Future research could explore how various metabolic states—such as those induced by diet, exercise, or disease—affect histone lactylation and innate immune memory. Moreover, understanding individual variability in these pathways could guide personalized vaccination strategies and immunotherapies. The interplay between microbiome-derived metabolites and host lactate signaling also represents an unexplored axis with potential relevance for mucosal immunity and systemic inflammation.
In conclusion, the work spearheaded by Netea and colleagues illuminates a crucial link between metabolism and epigenetics in human innate immunity. Lactate emerges not as a passive product but an active instructor shaping immune cell function through epigenetic remodeling. This discovery enriches the conceptual framework of trained immunity and opens transformative possibilities for vaccine science and immunological health interventions.
Subject of Research: People
Article Title: Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory
News Publication Date: 2-May-2025
Web References: http://dx.doi.org/10.1016/j.cell.2025.03.048
References: Ziogas A., Novakovic B., Ventriglia L., et al. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory. Cell. 2025.
Keywords: Trained immunity, innate immune memory, lactate, histone lactylation, epigenetics, BCG vaccine, metabolism, glycolysis, immune training, cytokine response
