How lactate and lactylation shape the immunity system in atherosclerosis (Review).

Cardiovascular diseases (CVDs), the leading cause of death worldwide, claims ~18 million lives each year and has high morbidity rates ( 1 - 4 ). Atherosclerosis is the main pathologic mechanism of most CVDs ( 5 ). These chronic plaques in vessel, composed mainly of cholesterol, fat, calcium and blood cells, gradually harden over time, leading to arterial stenosis and thereby restricting the flow of oxygen-rich blood to various parts of the body ( 6 ). Atherosclerosis has been found to be the central mechanism of this pathological process and the leading cause of CVDs worldwide ( 7 ). In recent years, atherosclerosis has been recognized as a chronic inflammatory disease and leads to arterial stenosis and plaque formation due to the accumulation of lipids and inflammatory cells within the arterial wall ( 8 - 11 ). The role of adaptive immunity in atherosclerosis has increasingly attracted attention ( 12 ). The adaptive immune system participates in the development of atherosclerosis through various cellular and molecular mechanisms, including the interactions of T cells ( 13 ), B cells ( 14 ), antigen-presenting cells ( 15 ) and cytokines ( 16 ). Inflammation plays a key role in the progression of atherosclerosis, and adaptive immune responses influence plaque formation and stability by modulating the activity of inflammatory cells and the secretion of cytokines. These studies further confirm the key role of inflammation and immunity in atherosclerosis and provide a theoretical basis for immune-modulating therapies. Epigenetics focuses on heritable changes in gene expression that are not derived from alterations in the nucleotide sequence, such as DNA or RNA methylation modifications, as well as post-translational modifications of proteins ( 17 ). Lactylation, an emerging post-translational modification, has garnered widespread attention in biological and medical research ( 18 - 20 ). Lactylation plays a crucial role in various biological processes, including the regulation of macrophage function, modulation of glycolytic activity and the promotion of tumorigenesis ( 21 ). As a key regulatory factor in numerous biological processes and disease mechanisms, lactylation modification has become a hot topic in molecular biology studies ( 22 , 23 ). Although the potential role of lactylation modification in CVD has been demonstrated ( 24 ), its role in regulating immunity in the context of atherosclerosis remains largely elusive. During the pathological process of atherosclerosis, the accumulation of lactate in local tissues obviously impacts this process. Therefore, vast research efforts have explored the interaction between lactylation modifications and adaptive immunity within the atherosclerotic microenvironment. This review aims to clarify the role of lactylation in immunity in the context of atherosclerosis and summarize the driving mechanisms. This article not only explores the roles of lactate and lactylation in atherosclerosis but also systematically analyzes their impacts on various components of the immune system, such as macrophages, T cells and B cells. To the best of our knowledge, this multidimensional perspective is relatively rare in previous reviews ( 12 , 25 - 27 ), as most studies have focused solely on a single cell type or mechanism. By closely integrating the metabolic characteristics of lactate with the regulation of immune responses, the article highlights the crucial role of metabolic reprogramming in atherosclerosis. This integrative approach provides a more comprehensive framework for understanding the pathogenesis of atherosclerosis. These innovative aspects not only enrich our understanding of the pathogenic mechanisms of atherosclerosis but also offer new directions for future therapeutic strategies.

In atherosclerotic plaques, high concentrations of lactate induce metabolic reprogramming in macrophages, shifting their metabolism from glycolysis to oxidative phosphorylation ( 159 - 161 ). This metabolic remodeling significantly impacts the functional status of macrophages: The accumulation of lactate inhibits mitochondrial function, reduces ATP production and consequently diminishes the activity and functional performance of macrophages ( 111 , 162 , 163 ). Furthermore, lactate induces the polarization of macrophages towards the M2 phenotype while inhibiting M1 polarization, thereby promoting their anti-inflammatory and immunosuppressive functions ( 164 , 165 ). Besides, lactate attenuates inflammatory responses by reducing the phosphorylation levels of NF-κB, thereby suppressing the transcription of inflammation-related genes ( 166 ). More critically, lactate can induce histone lactylation, a modification that regulates macrophage metabolism and phenotypic transformation by acting on both histones (such as H3K18la) and non-histone proteins (such as PKM2) ( 167 - 169 ). For instance, H3K18la modification activates the expression of M2-related genes and drives the transformation of M1 macrophages towards the M2 phenotype. Macrophage activation is one of the key features of atherosclerosis, typically accompanied by a shift in core metabolism from oxidative phosphorylation to glycolysis ( 19 ). It has been found that histone lactylation mediated by MCT4, which is associated with lactate efflux, is closely related to atherosclerosis. In the absence of MCT4, histone lactylation at lysine 18 of histone H3 activates the transcription of anti-inflammatory and TCA cycle genes, thereby initiating local repair and homeostasis ( 170 ). This finding indicates that lactylation plays an important role in regulating macrophage function and the progression of atherosclerosis. Lactate is a byproduct of glycolysis and usually accumulates in large amounts in the tumor microenvironment, creating an acidic ecological niche. In the acute inflammatory phase, lactate primarily exerts anti-inflammatory effects by activating the G protein-coupled receptor 81 receptor, thereby inhibiting the production of inflammatory mediators and alleviating the inflammatory response ( 171 , 172 ). However, the acidic environment caused by lactate accumulation exacerbates the persistence of inflammation and promotes tissue damage in the chronic inflammatory phase. Nevertheless, lactate also induces the polarization of immune cells and modulates metabolic pathways to facilitate the resolution of inflammation and exert certain anti-inflammatory effects ( 173 , 174 ). The activation and differentiation of T cells are accompanied by metabolic reprogramming, one of the metabolic hallmarks being aerobic glycolysis, which refers to the conversion of glucose to lactate in the presence of oxygen ( 175 ). T cells undergo metabolic reprogramming in different states of differentiation ( 176 ). For instance, effector T cells primarily rely on glycolysis, whereas regulatory T cells and memory T cells mainly depend on oxidative phosphorylation ( 177 , 178 ). T cells sense lactate through the expression of specific transporters, which leads to the inhibition of their migratory capacity. This 'stop signal' for migration depends on the interference of lactate with intracellular metabolic pathways, particularly glycolysis. Lactate promotes the differentiation of CD4+ T cells into the IL-17+ subset while reducing the cytotoxic capacity of CD8+ T cells. These phenomena lead to the formation of ectopic lymphoid structures at sites of inflammation and the production of autoantibodies ( 43 , 179 ). Lactate triggers the nuclear translocation of the PKM2 via an active transmembrane influx mediated by the sodium-coupled monocarboxylate transporter 2 (also known as solute carrier family 5 member 12). Within the nucleus, PKM2 forms a complex with phosphorylated signal transducer and activator of transcription 3, synergistically enhancing the transcriptional activity of the IL-17 gene, thereby markedly promoting IL-17 secretion by Th17 cells ( 180 - 182 ). The activity of Tregs relies on the metabolic reprogramming from glycolysis to oxidative phosphorylation, a process strictly regulated by the transcription factor forkhead box P3. Lactate promotes the accumulation of Tregs at inflammatory sites and activates the HIF-1α-dependent CCL20/CCR6 signaling axis, facilitating Treg migration to the lesion area. In addition, Tregs utilize lactate as a substrate for the TCA cycle, further enhancing their immunosuppressive function ( 164 , 183 , 184 ). Nevertheless, in chronic inflammatory responses, the persistent accumulation of lactate causes local tissue damage and drives the progression of chronic inflammation, which significantly exacerbates the pathological impact on atherosclerotic lesions and accelerates disease progression ( 173 , 179 ). Lactate plays a complex dual role in inflammation and immune responses. It exerts anti-inflammatory effects by regulating metabolism and immune cell functions, but it exacerbates tissue damage and disease progression in chronic inflammation. Lactylation promotes Th17 differentiation and participates in the development of autoimmune diseases and inflammatory responses by regulating site-specific modifications of key proteins such as IKAROS family zinc finger 1, which directly modulates the expression of Th17-related genes ( 185 ). In the tumor microenvironment, lactate regulates the generation of Treg cells through lactylation modification at lysine 72 of the MOESIN protein. This process enhances the interaction between MOESIN and transforming growth factor-β receptor I, activates the downstream SMAD3 signaling pathway and significantly improves the stability and function of Treg cells ( 186 ). This discovery provides an important reference for understanding the regulatory mechanisms of lactate accumulation on Treg cells in the context of atherosclerotic tissue environments. Lactate significantly inhibits the proliferation capacity and antibody production of B cells by reducing the extracellular pH ( 159 , 187 ). Additionally, lactate modulates the metabolic pathways of B cells, particularly by enhancing the glycolytic process, which provides rapid energy supply to support their proliferation and differentiation. At the same time, lactate suppresses oxidative phosphorylation and results in significant alterations in the metabolic state of B cells ( 28 , 188 ). At the molecular level, lactate promotes the growth and metabolic activities of B cells by activating the mammalian target of rapamycin signaling pathway ( 189 , 190 ). Under hypoxic conditions, lactate enhances the adaptability of B cells to low oxygen environments by stabilizing HIF-1α ( 191 - 193 ). Furthermore, lactate activates the NF-κB signaling pathway, promoting the secretion of pro-inflammatory cytokines by B cells, thereby participating in the regulation of inflammatory responses ( 194 , 195 ). These findings demonstrate that lactate plays a multifaceted role in the functional regulation of B cells, influencing metabolic reprogramming, signaling pathway activation and environmental adaptability, among other aspects. Lactylation modulates the antibody class switch recombination (CSR) in B cells by influencing metabolic pathways. For instance, the MCT1-mediated lactate transport and pyruvate metabolism regulates the acetylation modification of histone H3K27, thereby affecting the transcriptional efficiency of activation-induced cytidine deaminase, which ultimately impacts the CSR in B cells ( 196 ) ( Fig. 4 ). Lactate and its mediated lactylation modifications play a complex dual role in atherosclerosis by regulating metabolic reprogramming, functional polarization and epigenetic modifications of macrophages, T cells and B cells.

In summary, this review comprehensively analyzes the multifaceted roles of lactate and lactylation in shaping the immune system within the context of atherosclerosis. As a chronic inflammatory disease, atherosclerosis is characterized by the complex interplay between lipid metabolism, immune cell infiltration and the local microenvironment. The results highlight the critical roles of lactate and lactylation in modulating immune cell functions, metabolic reprogramming and epigenetic regulation, thereby influencing the progression and stability of atherosclerotic plaques. The involvement of lactate and lactylation in the regulation of macrophage polarization, T cell differentiation and B cell metabolism underscores their potential as therapeutic targets. Specifically, lactate-induced metabolic reprogramming and lactylation modifications have been shown to significantly impact the phenotypes and functions of immune cells and contribute to pro-inflammatory and anti-inflammatory responses. These insights provide a deeper understanding of the immune metabolic mechanisms underlying atherosclerosis and pave the way for novel therapeutic strategies targeting lactate metabolism and lactylation pathways. However, despite the progress made in elucidating the roles of lactate and lactylation in atherosclerosis, several gaps remain in our knowledge. The complex microenvironment of atherosclerotic plaques, characterized by hypoxia, nutrient deprivation and acidosis, is likely to influence the behavior of immune cells and the efficacy of potential treatments. Yet, the precise mechanisms through which these microenvironmental factors interact with lactate and lactylation to modulate immune responses are still not fully understood. Additionally, the diverse metabolic profiles and functional states of immune cells within plaques suggest that a more detailed characterization of immune cell subsets and their specific roles is needed. Furthermore, the dynamic changes in the atherosclerotic microenvironment over time, from plaque initiation to rupture, add another layer of complexity to the study of immune regulation. The impact of these temporal changes on lactate production, lactylation modifications and immune cell function remains elusive. Furthermore, the potential compensatory mechanisms and feedback loops involving other metabolic pathways and epigenetic modifications in response to lactate accumulation and lactylation need further investigation. In conclusion, although significant advancements have been made in understanding the roles of lactate and lactylation in atherosclerosis, the intricate interplay between the microenvironment, metabolic changes and immune regulation remains an area of considerable research need. Future studies should focus on unraveling the detailed mechanisms through which the atherosclerotic microenvironment influences lactate metabolism and lactylation, as well as their downstream effects on immune cell function. These will enhance our understanding of the pathophysiology of atherosclerosis and provide new avenues for developing targeted therapies aimed at modulating immune responses and improving clinical outcomes.