The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity

Yanjie Li; Mingzhu Chen; Junxiong Li; Jiangtian Hu

doi:10.2147/JIR.S513325

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Review

The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity

Authors Li Y, Chen M, Li J, Hu J

Received 19 December 2024

Accepted for publication 22 May 2025

Published 13 June 2025 Volume 2025:18 Pages 7795—7811

DOI https://doi.org/10.2147/JIR.S513325

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Durga Prasanna Misra

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Yanjie Li,^1,² Mingzhu Chen,^1,² Junxiong Li,^1,² Jiangtian Hu^1,²

¹Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, People’s Republic of China; ²Yunnan Key Laboratory of Stomatology, Kunming, 650106, People’s Republic of China

Correspondence: Jiangtian Hu, Email [email protected]

Abstract: Pattern recognition receptors (PRRs) function as pivotal components of the innate immune system by orchestrating trained immunity through dynamic epigenetic and metabolic reprogramming. Recent discoveries demonstrate that PRRs not only detect pathogens but also actively regulate immune cell metabolism and transcriptional landscapes, thereby potentiating the speed and magnitude of defensive responses upon secondary challenges. These functional adaptations are coordinated through evolutionarily conserved signaling cascades that establish persistent immunological modifications at cellular and systemic levels. Nevertheless, despite substantial advances in characterizing PRR-driven immune activation, the molecular mechanisms governing their role in innate immune memory formation remain incompletely elucidated. This review systematically explores emerging paradigms of PRR-mediated epigenetic remodeling and metabolic rewiring, with particular emphasis on their mechanistic integration into trained immunity. We critically assess current evidence, identify unresolved questions regarding signal transduction specificity and memory maintenance, and propose novel methodological approaches to decipher the multilayered regulatory networks of innate immune adaptation. By elucidating these processes, our analysis establishes a conceptual framework for developing immunomodulatory therapies and leveraging trained immunity in precision medicine applications.

Keywords: pattern recognition receptors, epigenetic, metabolic reprogramming, trained immunity, immunocyte

Introduction

Trained immunity (TI) is an evolutionarily conserved mechanism of innate immune memory that enhances nonspecific host defense through epigenomic and metabolic reprogramming. Unlike the antigen-specific memory conferred by adaptive immunity via T and B lymphocytes, TI predominantly engages myeloid lineage cells, including monocytes and macrophages. This functional rewiring is initiated through activation of germline-encoded PRRs, particularly Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which recognize conserved pathogen-associated molecular patterns (PAMPs). PRR signaling triggers chromatin remodeling events characterized by histone modifications such as H3K4 trimethylation (H3K4me3), coupled with metabolic shifts toward aerobic glycolysis. These coordinated changes establish a transcriptionally permissive state for rapid cytokine gene activation, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). While adaptive immune memory provides lifelong protection, TI generally exhibits a shorter duration spanning weeks to months. Notably, dietary metabolites like β-glucans modulate the magnitude and persistence of TI by targeting epigenetic modifiers within transcriptional regulatory complexes. Thus, PRRs function as biochemical integrators that convert microbial encounters into sustained immune reprogramming. This paradigm shift in innate immune plasticity not only challenges traditional immunological frameworks but also offers novel therapeutic strategies for infectious diseases, cancer immunotherapy, and inflammation-related pathologies.^1,2

As central architects of immune memory, PRRs detect both PAMPs and damage-associated molecular patterns (DAMPs) to execute dual functions: triggering immediate host defense mechanisms^3,4 and coordinating sustained epigenetic-metabolic reprogramming for innate immune memory.^5–7 The activation of PRRs induces two mutually reinforcing processes—dynamic metabolic rewiring and stable epigenetic modifications—that synergistically enhance immune cell responsiveness to secondary challenges.^8,9 These molecular adaptations amplify antimicrobial effector functions while promoting cytokine production, creating metabolic-epigenetic imprints essential for TI establishment. Experimental models demonstrate that PRR recognition of bacterial components establishes persistent antimicrobial memory in myeloid cells, conferring robust protection against reinfection.^10–12 Such insights hold transformative potential for designing next-generation vaccines and immunotherapies.¹³

Critical knowledge gaps persist in deciphering PRR-mediated training mechanisms. Existing studies predominantly focus on PRR functions in pathogen detection and acute inflammatory signaling, with limited investigation into their roles in maintaining and regulating immune adaptation. Furthermore, the tissue-specific expression profiles and functional diversification of PRR subsets remain poorly characterized, particularly in pathological contexts such as chronic inflammation, autoimmunity, and tumor microenvironments.

Classification and Function of Pattern Recognition Receptors

Toll-Like Receptors (TLRs)

TLRs, recognized as the prototypical and evolutionarily conserved family of transmembrane PRRs, are classified into 13 functional subtypes in mice (TLR1-TLR13) and 10 in humans (TLR1-TLR10), based on their ligand specificity and subcellular localization. Cell membrane-resident TLRs—specifically TLR1, TLR2, TLR4, TLR5, and TLR6—primarily detect microbial membrane components such as bacterial lipoproteins (TLR1/2/6), lipopolysaccharide (LPS, sensed by TLR4), and flagellin (TLR5). In contrast, intracellular TLRs localized to endosomal compartments (TLR3, TLR7, TLR8, and TLR9) recognize viral nucleic acids including double-stranded RNA (TLR3), single-stranded RNA (TLR7/8), and unmethylated CpG DNA (TLR9).^14–16 Upon LPS binding, TLR4 undergoes dimerization and recruits the adaptor protein Myeloid Differentiation Primary Response 88 (MyD88) via Toll/Interleukin-1 Receptor (TIR) domain interactions, initiating a multi-step signaling cascade. MyD88 mediates the assembly of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), which subsequently phosphorylates and activates Interleukin-1 Receptor-Associated Kinase 1 (IRAK1). This kinase activation leads to nuclear translocation of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). These coordinated events drive the transcriptional upregulation of pro-inflammatory cytokines such as TNF-α and IL-6, along with chemokines critical for immune cell recruitment.^17,18

Expanding beyond microbial defense, emerging evidence reveals context-dependent roles of TLRs in tumor immunobiology. TLR agonists demonstrate dual functionality in oncological settings: they potentiate γδ T cell-mediated antitumor activity either directly or via dendritic cell activation, and synergize with tumor-associated antigens to enhance cytotoxic T lymphocyte (CTL) responses. Preclinical studies illustrate this therapeutic potential, as combined administration of TLR9 agonist CpG oligodeoxynucleotides (CpG ODN) with rlipo-E7m effectively amplifies CTL activity and achieves regression of established tumors.^19–21

Nucleotide-Binding Oligomerization Domain-Like Receptors (NLRs)

NLRs are critical cytosolic PRRs orchestrating innate immune responses and inflammatory regulation. The NLR family is structurally classified into five subfamilies: (1) NLRA (characterized by an acidic transactivation domain, exemplified by class II transactivator, CIITA), (2) NLRB (bearing baculovirus inhibitor of apoptosis protein repeat, BIR, domains, as observed in neuronal apoptosis inhibitory protein, NAIP), (3) NLRC (containing caspase activation and recruitment domains, CARD, including nucleotide-binding oligomerization domain-containing proteins 1 and 2, NOD1 and NOD2, that activate NF-κB, and Mitogen-Activated Protein Kinase, MAPK, pathways through receptor-interacting serine/threonine-protein kinase 2, RIPK2, and transforming growth factor beta-activated kinase 1, TAK1, signaling complexes), (4) NLRP (defined by pyrin domain-containing members such as NLRP1 and NLRP3), and (5) NLRX (localized to mitochondrial membranes).^22,23 Functioning as intracellular surveillance systems, NLRs detect PAMPs from invading microbes and DAMPs released by stressed or necrotic cells, serving as central hubs for cytosolic danger signal integration.^24–27 Mechanistically, specific NLR subfamilies – particularly NLRP3 – nucleate inflammasome complexes that catalyze caspase-1-dependent proteolytic maturation of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), key pro-inflammatory cytokines essential for driving leukocyte infiltration and tissue remodeling during microbial challenges.^28–30 Beyond antimicrobial defense, NLRs maintain tissue homeostasis through strict governance of inflammatory responses. Pathological NLR activation disrupts this equilibrium, as demonstrated by inflammasome hyperactivity in autoimmune disorders including rheumatoid arthritis and inflammatory bowel disease, where IL-1β/IL-18 overproduction directly correlates with disease progression.^31–33 Emerging evidence implicates NLRP3 inflammasome dysregulation in chronic disease pathogenesis. In cardiovascular pathologies, persistent NLRP3 activation induces endothelial dysfunction and plaque instability, while in neurodegenerative conditions such as Alzheimer’s disease, it potentiates neuroinflammatory cascades and amyloid-beta deposition.^34,35 These mechanistic insights establish NLR-mediated signaling pathways as promising therapeutic targets for chronic inflammatory diseases, either through direct inflammasome inhibition or downstream cytokine neutralization strategies.

C-Type Lectin Receptors (CLRs)

CLRs, as specialized PRRs, utilize conserved carbohydrate-recognition domains (CRDs) to detect pathogenic glycans (microbial-associated molecular patterns) and host damage signals. These receptors exist in membrane-bound (including CLEC7A and CLEC4E) and soluble forms (mannose-binding lectin), performing dual surveillance of exogenous microbial components (fungal β-glucans, mycobacterial glycolipids, viral glycoproteins) and endogenous glycocalyx integrity. Functionally, CLRs bridge innate and adaptive immunity through two distinct mechanisms: (1) Signal transduction via Syk-coupled CLRs: Specific members such as CLEC7A activate NF-κB/MAPK/IRF-mediated proinflammatory and antiviral pathways through β-glucan-induced signal transduction. This process initiates SYK kinase recruitment, followed by assembly of the caspase recruitment domain-containing protein 9 (CARD9)/B-cell lymphoma 10 (BCL10)/mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) ternary complex, ultimately driving TGF-β-activated kinase 1 (TAK1)-dependent downstream cascades. (2) Antigen presentation via endocytic CLRs: Receptors like DEC-205 facilitate dendritic cell-dependent antigen processing and presentation, thereby priming T-cell adaptive responses.^36,37

Crucial for antifungal immunity, CLRs mediate recognition of clinically significant pathogens including Candida albicans and Aspergillus species through binding of surface carbohydrates, subsequently activating macrophages and dendritic cells to initiate pathogen clearance.^38–40 This interaction induces proinflammatory cytokine/chemokine production essential for leukocyte recruitment and coordinates dendritic cell maturation, thereby establishing innate-to-adaptive immune crosstalk.^41,42

Emerging evidence expands CLR functionality in tumor immunology. Acting as multimodal regulators, CLRs modulate the tumor microenvironment by recognizing tumor-associated glycosylation patterns (mannose structures, Lewis antigens, GalNAc). These receptors exhibit dualistic roles in carcinogenesis: (a) tumor-suppressive through antigen-presenting cell-mediated immune activation, and (b) tumor-promoting via metastatic facilitation of malignant cells.^43,44 Furthermore, CLRs mediate endocytic antigen processing and directly regulate T-cell activation thresholds. Therapeutic strategies targeting CLRs are under investigation, including Clec4e/Dectin-1 blocking antibodies that attenuate neutrophil-mediated tumor cytotoxicity in murine models.^45,46

RIG-I-Like Receptors (RLRs)

The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), constituting a specialized subclass of cytosolic RNA-sensing PRRs, detect viral nucleic acids via conserved helicase and C-terminal regulatory domains. This receptor family comprises three structurally defined members: RIG-I (specific for short 5′-triphosphate RNA/dsRNA), MDA5 (selective for long dsRNA), and the regulatory co-factor LGP2, collectively executing viral RNA surveillance through discrimination of pathogen signatures (eg, unshielded 5′-triphosphates) from host RNA degradation products.^47,48

Mechanistically, RLR activation requires CARD domain-mediated oligomerization with the mitochondrial antiviral-signaling protein (MAVS). Recent structural insights demonstrate that the CARD:CARD interface between RLRs (specifically RIG-I and MDA5) and MAVS adopts a helical filamentous architecture, which serves as a supramolecular signaling platform (MAVS signalosome) by nucleating prion-like aggregates. This receptor-proximal interaction topology (RLR CARD helices engaging MAVS CARD surface grooves) enables tightly regulated signal amplification, where dynamic ubiquitination switches (TRIM25-mediated K63-ubiquitin chain deposition on RIG-I CARDs versus CYLD-mediated deubiquitination) and competitive inhibition (eg, NLRX1 C-terminal domain sterically blocking MAVS CARD accessibility) synergistically control antiviral response thresholds.^49,50 Activation of the MAVS signalosome recruits the TAK1 kinase complex, which bridges RLR-induced mitochondrial signaling to downstream NF-κB and MAPK pathways^48,51 (Figure 1).

Figure 1 PRRs regulate intracellular immune responses and trigger the release of pro-inflammatory cytokines and interferons. LPS activates TLR4 to recruit TIRAP and MyD88, forming a complex that phosphorylates IRAK4 and IRAK1, leading to activation of the NF-κB pathway for pro-inflammatory gene transcription. NOD1/2 recognize bacterial ligands (iE-DAP/MDP) and engage RIP2, which orchestrates TAK1 complex-dependent activation of NF-κB and MAPK pathways to amplify cytokine responses. CLRs detect β-glucans and trigger assembly of the CARD9/BCL10/MALT1 signaling complex, which activates TAK1-mediated NF-κB and MAPK pathways. RLRs bind viral RNA to induce MAVS aggregation, activating TAK1 for NF-κB/MAPK signaling and recruiting TBK1/IKKε kinases to phosphorylate IRF3/IRF7, thereby promoting interferon synthesis. (Created with Figdraw).

Epigenetic Regulatory Mechanisms

DNA Methylation

DNA methylation, a fundamental epigenetic modification, involves the enzymatic transfer of methyl groups (-CH₃) to cytosine residues within cytosine-phosphate-guanine (CpG) islands—genomic regions enriched in cytosine-guanine dinucleotide repeats. This covalent modification induces transcriptional silencing through dual mechanisms: chromatin condensation and steric hindrance of transcription factor binding.^52,53 Unlike transient transcriptional fluctuations, persistent methylation anomalies demonstrate causal involvement in diverse pathologies ranging from neoplastic progression (including breast and cervical carcinomas) to cardiovascular diseases and metabolic dysregulation.^54–56

Pathological epigenetic reprogramming predominantly operates through two molecular axes: (1) promoter hypermethylation-mediated inactivation of tumor suppressor genes (exemplified by MRVI1 and NTRK3 silencing during cervical carcinogenesis), and (2) DNA methyltransferase (DNMT)-dependent dysregulation of non-coding RNAs. The latter mechanism is typified by hypermethylation-induced suppression of tumor-suppressive microRNAs (miR-29c, miR-200c, and miR-200a) that confers chemoresistance in breast adenocarcinoma.^57,58 Beyond transcriptional control, methylation dynamics orchestrate cellular differentiation, developmental morphogenesis, and environmental adaptation through spatiotemporal methylome remodeling.^59–61 Advanced methylome profiling technologies—bisulfite sequencing, single-cell methylomics, and nanopore-based detection—now enable high-resolution mapping of disease-associated epimutations. These methodologies systematically identify functionally relevant methylation signatures at loci such as CDKN2A/p16 (cell cycle regulation) and MLH1 (DNA repair).^62,63 Such epigenomic insights facilitate two therapeutic strategies: pharmacological DNMT inhibition (decitabine and azacitidine) and precision epigenetic editing using CRISPR-dCas9 systems targeting aberrantly methylated promoters.

Histone Modification

Histone modification serves as a crucial epigenetic regulatory mechanism through chemical modifications such as methylation, acetylation, and phosphorylation, which influence chromatin structure and regulate gene accessibility and expression.^64,65 Distinct histone modifications exert specific regulatory effects. For example, histone H3 acetylation generally activates gene transcription, whereas H3 methylation predominantly represses transcriptional activity. As a key metabolic byproduct, lactate enhances histone H3K27 acetylation, thereby activating nuclear receptor subfamily 4 group A member 1 (Nr4a1) and suppressing pro-inflammatory pathways in macrophages. This lactate-induced acetylation mediates sustained “trained immunosuppression” by establishing long-term chromatin remodeling. Furthermore, nucleosomes physically block DNMTs from accessing DNA, thereby limiting DNMT-mediated transcriptional repression.^66,67

Dynamically regulated histone modifications coordinate essential biological processes, including cell cycle progression and DNA damage repair, through chromatin state transitions.^68,69 These modifications precisely govern cellular functions such as proliferation, differentiation, and apoptosis. In cancer biology, aberrant histone modification landscapes drive tumorigenesis by silencing tumor suppressor genes and activating oncogenic pathways.^70,71 Consequently, therapies targeting these dysregulated mechanisms—notably histone deacetylase (HDAC) inhibitors—are emerging as effective anticancer strategies through epigenetic reprogramming and synergistic interactions with immunotherapy.⁷²

Role of Non-Coding RNAs

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in epigenetic regulation through diverse mechanisms such as direct mRNA interactions and transcription factor modulation.^73–75 Specific subtypes exert distinct regulatory functions: miRNAs primarily post-transcriptionally regulate gene expression through mRNA degradation or translational inhibition, profoundly influencing immunometabolic reprogramming processes including glycolysis and oxidative phosphorylation.^76–78 Conversely, lncRNAs coordinate epigenetic regulation through chromatin remodeling mechanisms by altering histone modification patterns and DNA methylation status, thereby directly controlling immune cell metabolism and trained immunity programs. For example, lncRNA-SNHG29 orchestrates genome-wide binding of EP300 (a histone acetyltransferase critical for metabolic reprogramming) to drive glycolytic activation in myeloid cells during innate immune responses, while lncRNA-GTL2 mediates DNA methylation-dependent silencing of fatty acid oxidation genes in macrophages, illustrating the metabolic-epigenetic crosstalk in trained immunity.^79,80

Notably, ncRNA dysregulation contributes significantly to tumorigenesis and cancer progression, frequently intersecting with immune cell metabolic pathways such as the Warburg effect.^81,82 These molecules demonstrate promising potential as diagnostic biomarkers due to their tissue-specific expression profiles, with emerging applications in cancer screening and prognostic assessment.^83,84 With increasing mechanistic understanding, ncRNA-targeted therapeutic strategies are under active exploration, particularly approaches modulating lncRNAs to normalize dysregulated immunometabolic pathways for precise disease intervention.^85–87

PRRs Mediate Epigenetic Reprogramming of Immune Cells

PRR activation triggers profound chromatin reorganization and transcriptional remodeling in immune cells, establishing a primed state that enhances responsiveness to secondary challenges through amplified immune reactions. Mechanistically, PRR-mediated signaling orchestrates multi-layered epigenetic regulation via transcription factor modulation and chromatin modifications, including histone acetylation, methylation, and nucleosome repositioning.^88,89 The evolutionarily conserved TIR domain present in TLRs and related PRRs functions as a molecular scaffold for downstream adaptor recruitment (eg, MyD88, TRIF), initiating signal transduction. During LPS stimulation, TLR4 TIR domain acetylation facilitates oligomerization-enhanced adaptor binding, dramatically amplifying NF-κB signaling through IRAK4 activation and accelerated Inhibitor of Nuclear Factor kappa-B alpha (IκBα) degradation, reinforcing M1 macrophage polarization.⁹⁰

TLR activation by LPS induces not only pro-inflammatory mediators but also persistent epigenetic signatures. IL-4-polarized macrophages subjected to LPS develop epigenetically encoded hyper-inflammatory programs, with sustained H3K27ac-driven transcriptional memory exacerbating pulmonary inflammation upon TLR rechallenge.⁹¹ This TIR signaling-epigenetic crosstalk mechanistically links innate immune activation to metabolic-epigenetic memory. Primary inflammatory stimuli imprint microglial immune memory via H3K27ac, while pharmacological inhibition of this mark prevents secondary inflammatory amplification.⁹² Tet methylcytosine dioxygenase 2(TET2) exerts epigenetic control in atherogenesis, where TET2 deficiency enables cholesterol-loaded macrophages to activate NLRP3 via c-Jun N-terminal kinase 1(JNK1) signaling and BRCA1-Associated Protein 1(BRCC3)-mediated deubiquitination.⁹³

Recent studies demonstrate that PRR activation by microbial components can synergize with exogenous therapeutic interventions. For example, β-glucan-induced Dectin-1 signaling primes H3K27 acetylation at glycolytic gene loci,⁹⁴ a process that may amplify the metabolic effects of vitamin D adjuvants, which are known to enhance TLR2-mediated H3K4me3 deposition.^95,96 In oncological contexts, TLR3-activated IRF3 directly remodels antiviral response elements through interactions with oncolytic virus-derived RNA,⁹⁷ while CpG/TLR9 agonists have demonstrated clinical efficacy in eradicating cancer stem cells when combined with epigenetic checkpoint inhibitors.^98,99 These findings position PRR signaling as a highly tunable epigenetic scaffold for developing combination immunotherapies.

Metabolic Reprogramming

Metabolic reprogramming refers to the adaptive rewiring of cellular metabolic pathways to meet biosynthetic and bioenergetic demands under specific environmental or pathological conditions. This phenomenon has been systemically characterized across oncology, immunology, and metabolic disorders.^100–102 Through coordinated regulation of nutrient utilization and energy flux, cells dynamically reconfigure metabolic networks to sustain proliferation, survival, and effector functions. A hallmark example is the “Warburg effect” in malignancies, where tumor cells preferentially upregulate aerobic glycolysis despite functional mitochondria, concurrently suppressing oxidative phosphorylation to fuel anabolic growth and metastatic dissemination.^103–105

In immunometabolic contexts, immune-responsive gene 1 (IRG1)-derived itaconic acid, synthesized by macrophages under pro-inflammatory stimuli (eg, LPS or IFN-γ), modulates T cell plasticity through dual mechanisms: (1) direct suppression of glycolysis and (2) epigenetic regulation, collectively ameliorating autoimmune pathologies. Furthermore, IgG FcγR-mediated macrophage metabolic reprogramming, marked by mTOR- and HIF-1α-driven glycolytic upregulation, has emerged as a targetable axis in lupus nephritis. Within breast cancer microenvironments, hypoxia and nutrient competition drive tumor-associated macrophages (TAMs) to impede CD8+ T cell function via collagen accumulation and lactate-mediated metabolic interference (eg, disruption of oxidative phosphorylation), illustrating how spatial metabolic coupling dictates immune evasion.^106–108 These adaptive mechanisms not only underpin disease progression and immune dysregulation but also reveal novel therapeutic vulnerabilities. Key targets include the IRG1-itaconic acid signaling axis, rate-limiting glycolytic enzymes (eg, hexokinase 2, HK2), and lactate transport systems, offering multimodal intervention strategies across pathological states.

The Role of PRR in Metabolic Reprogramming

The activation of PRRs serves dual biological roles: modulating immune cell functions and orchestrating context-dependent metabolic reprogramming.^109,110 For instance, the TLR4 agonist LPS and other TLR ligands rapidly enhance the enzymatic activity of class IIa histone deacetylases (HDAC4, HDAC5, HDAC7, and HDAC9). This activity suppresses glycolysis and amplifies inflammatory responses by deacetylating key glycolytic enzymes such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3).¹¹¹ Additionally, TLR4 activation may inhibit AMP-activated protein kinase (AMPK) function by altering intracellular metabolic states. Given AMPK’s anti-inflammatory role in suppressing pro-inflammatory mediators like NF-κB, this inhibition helps mitigate inflammation triggered by TLR signaling.¹¹² TLR signaling also modulates oxidative phosphorylation (OXPHOS) through the Phosphoinositide 3-kinase (PI3K)- Protein kinase B (AKT) and Janus kinase (JAK)- Signal Transducer and Activator of Transcription (STAT) pathways, which are mechanistically linked to reactive oxygen species (ROS) generation. Such regulation augments OXPHOS and ROS production, ultimately enhancing antitumor immunity.¹¹³ Beyond TLRs, other PRRs—including CLRs and RLRs—regulate immune cell metabolism via distinct mechanisms involving OXPHOS, amino acid metabolism, and mitochondrial dynamics. These findings underscore PRR-driven metabolic reprogramming as a source of therapeutic potential.¹¹⁴ Targeting specific pathways, such as glycolysis, OXPHOS, or amino acid metabolism, could enable precise immunomodulation, exemplified by small-molecule inhibitors of HDACs or AMPK modulators, offering novel avenues for therapeutic intervention.^115,116

Association of Metabolic Pathways with the Immune Response

Metabolic pathways are intricately intertwined with immune responses, as immune cells undergo metabolic reprogramming upon activation to sustain functional demands. This reprogramming not only fulfills the bioenergetic requirements of immune cells but also critically governs cytokine production and secretion by modulating signaling cascades, thereby enabling effective immune effector functions.^117–119 For example, macrophage phenotypic transitions are profoundly shaped by metabolic adaptation. Lactate enhances Pyruvate Kinase M2 (PKM2) lactylation, which inhibits its structural shift from tetrameric to dimeric states. This increases pyruvate kinase enzymatic activity while reducing PKM2 nuclear translocation, thereby driving pro-inflammatory macrophages toward a reparative phenotype.¹²⁰ Similarly, CH25H (cholesterol-25-hydroxylase)-mediated accumulation of 25-hydroxycholesterol (25HC) activates AMPKα and reprograms macrophage metabolism, which augments STAT6 activity to induce the immunosuppressive factor ARG1 (arginase 1).¹²¹ In tolerogenic dendritic cells, Mammalian Target of Rapamycin (mTOR):AMPK phosphorylation balance shifts and increased OXPHOS, glycolysis, and fatty acid oxidation collectively establish an immunosuppressive phenotype characterized by PD-L1 and IL-10 upregulation to suppress T cell activation.¹²²

The tumor microenvironment (TME) exemplifies the bidirectional crosstalk between metabolism and immune function. Tumor cells subvert immune surveillance by reshaping metabolic landscapes through mechanisms such as lactate accumulation and nutrient depletion, which directly impair immune cell efficacy.^123–125 Such metabolic rewiring constitutes a pivotal axis of tumor immune evasion and a persistent barrier to successful immunotherapy.^126,127 Therapeutic targeting of immune cell metabolism has emerged as a promising strategy. For instance, tumor-infiltrating T cells (TILs) are metabolically compromised in the TME due to metabolites like fatty acids that chronically activate acetyl-CoA carboxylase (ACC). ACC hyperactivity disrupts mitochondrial energy synthesis required for antitumor activity. Pharmacological ACC inhibition reverses these defects, restores TIL functionality, and enhances tumor control.^128,129 Similarly, TAMs exhibit metabolic heterogeneity, with elevated purine metabolism being a hallmark of their pro-tumorigenic phenotype, positioning this pathway as a therapeutic vulnerability.¹³⁰

Dietary factors further modulate TI plasticity. Short-chain fatty acids (SCFAs) from dietary fiber fermentation enhance β-glucan-induced TI by stabilizing HIF-1α-dependent histone acetylation in monocytes.¹³¹ Conversely, high-fat diets suppress TI by disrupting TLR4-driven enhancer-promoter looping via PPARγ activation.¹³² These insights collectively underscore TI as a dynamic interface between environmental cues and immune memory, where PRRs act as epigenetic sensors to transduce nutrient signals into functional immune adaptations.

Effects of PRRs on Trained Immunity

Primary Infection and Activation of Immune Cells

The initial infection represents a pivotal phase in the establishment of TI. During this stage, pathogens breach host barriers via the skin or mucosal surfaces, initiating a cascade of immune reactions. Macrophages and dendritic cells detect these pathogens through PRRs, triggering their activation.^133–135 Beyond immediate pathogen clearance through phagocytosis and neutralization, these cells amplify immune responses by recruiting additional effectors via cytokine secretion.¹³⁶ A hallmark of TI is the persistent metabolic and epigenetic remodeling of immune cells post-infection, which establishes an immune “memory”. This programming enables heightened responsiveness to subsequent encounters with homologous or heterologous pathogens.^137,138 For example, Drosophila primed with low-pathogenicity bacteria exhibit markedly improved survival upon secondary challenge with virulent strains, illustrating conserved cross-protective mechanisms.¹³⁹ Immunostimulatory adjuvants targeting TLRs or other PRRs amplify Antigen-Presenting Cell (APC) activation and maturation, thereby enhancing antigen presentation and co-stimulatory signal generation to fortify innate immune efficacy^140,141 (Figure 2).

Figure 2 Comparison of trained immunity and adaptive immunity in immune responses. (a) Trained immunity: First exposure of innate immune cells to PAMPs induces a moderate initial response (first peak). Secondary challenge with heterologous stimuli triggers an amplified response (second peak), mediated by epigenetic modifications and metabolic shifts (enhanced glycolysis/TCA cycle activity). (b) Adaptive immunity: Antigen-specific recognition by T/B cells via TCR/BCR activates clonal expansion. Upon re-exposure to the same antigen, memory T/B cells rapidly proliferate and produce high-affinity antibodies (B cells) or cytokine/cytolytic responses (T cells). This memory relies on genetic recombination (V(D)J diversification in antigen receptors) and MHC-mediated antigen presentation to ensure specificity. (Created with Figdraw).

PRRs Regulate Trained Immunity Through the Interplay Between Metabolic Reprogramming and Epigenetics

PRRs are indispensable for immune cell activation and functional modulation. Emerging evidence demonstrates that PRRs not only drive classical immune signaling but also mediate trained immunity (TI) through crosstalk with metabolic and epigenetic networks.^142–144 TI is characterized by heightened immune responsiveness to secondary pathogenic challenges, driven by persistent metabolic and epigenetic adaptations following initial stimulatory events.^145,146 PRR signaling activates RNA polymerase II (RNPII) and Polycomb repressive complex 2 (PRC2), driving epigenetic modifications such as histone methylation (eg, H3K27me3) and acetylation to regulate the accessibility of pro-inflammatory and antiviral genes.^147,148 These processes are finely modulated by key metabolites including S-adenosylmethionine (SAM), acetyl-CoA, Nicotinamide Adenine Dinucleotide (NAD⁺), and pyruvate. For instance, glucose and acetate-derived acetyl-CoA fuel the TCA cycle, altering metabolic flux dynamics to influence the NAD⁺/ Nicotinamide Adenine Dinucleotide + Hydrogen (NADH) ratio, which activates deacetylases like Sirt1 to balance histone acetylation during inflammation resolution.^149,150 PRR activation induces metabolic rewiring in immune cells, reconfiguring energy utilization pathways. For example, macrophages undergo a metabolic switch from OXPHOS to aerobic glycolysis, rapidly generating ATP to sustain effector functions while modulating inflammatory polarization.^151,152 This glycolytic shift not only meets bioenergetic demands but also fuels epigenetic remodeling via metabolites such as acetyl-CoA and SAM.^153–155 Acetyl-CoA serves as a critical substrate for histone acetylation, amplifying acetylation levels to derepress cytokine genes (eg, IL-6, TNF-α, IL-1β), thereby potentiating pathogen-responsive capacity.¹⁵⁶ Beyond metabolic regulation, acetyl-CoA orchestrates inflammatory gene expression via a metabolic-epigenetic axis. TLR4 activation, for instance, upregulates glycolysis and tricarboxylic acid (TCA) cycle activity in macrophages, converting glucose-derived carbons into acetyl-CoA. This metabolite enhances histone acetylation at loci encoding LPS-induced pro-inflammatory mediators (eg, TNF-α, IL-6, NLRP3), fine-tuning transcriptional outputs.¹⁵⁷

Moreover, PRR signaling reprograms the epigenetic landscape of immune cells to synchronize metabolic plasticity with immunological memory. The SET domain-containing protein 7 (SET7) methyltransferase catalyzes monomethylation of H3K4me1, regulating both immune gene transcription and OXPHOS-associated metabolic pathways. Crucially, metabolic intermediates (eg, pyruvate) cooperate with epigenetic regulators (eg, AP-1, NF-κB) to amplify the expression of pro-inflammatory cytokines (eg, TNF-α, IL-6) and type I interferons (IFN-α/β), establishing a multi-layered immune response network.¹⁵⁸ Sustained OXPHOS-linked metabolic adjustments establish a “metabolic memory”, enabling rapid reactivation of immune cells upon secondary pathogen encounters and reinforcing memory-driven protection.¹⁵⁹ The synergistic interplay between metabolic remodeling and epigenetic regulation underpins immediate immune effector functions and long-term adaptive priming. PRR-triggered metabolic-epigenetic integration thus emerges as a central mechanism for enhancing immune memory and shaping the pathogenesis of immune-mediated diseases (Figure 3).

Figure 3 PRRs regulate trained immunity via epigenetic and metabolic reprogramming. Pathogen recognition via PRRs activates transcription machinery (eg, RNA polymerase II) and epigenetic modifiers (eg, Polycomb Repressive Complex 2, PRC2), inducing histone acetylation and methylation to prime immune gene loci. Key metabolites such as acetyl-CoA (generated from glucose and acetate), NAD+, and pyruvate fuel the TCA cycle, regulating the NAD+/NADH ratio and modulating sirtuin deacetylases (eg, Sirt1). These metabolic shifts synergize with chromatin remodeling to enhance transcriptional activation of pro-inflammatory cytokines (eg, IL-6, TNF-α) and type I interferons (IFN-α/β). Transcription factors (AP-1, NF-κB) further amplify immune gene expression, establishing a prolonged antimicrobial state. (Created with Figdraw).

Conclusion

TI, an adaptive memory-like response of innate immune cells, exhibits dualistic roles in host defense and pathological processes. This adaptive process proceeds through a hierarchical cascade: initial pathogen exposure triggers metabolic reprogramming (eg, glycolytic upregulation), yielding metabolites such as acetyl-CoA and α-ketoglutarate (α-KG), which serve as enzymatic cofactors for epigenetic remodeling, including histone acetylation and H3K4me1 deposition. These changes collectively prime immune cells for heightened responsiveness to secondary stimuli. Studies highlight TI’s protective capacity; for example, dimethyl itaconate administration post-Staphylococcus aureus infection reprograms glycolytic and mitochondrial metabolism in murine models, enhancing microbial ligand sensitivity and survival outcomes.¹⁶⁰ Similarly, β-glucan-trained lung macrophages inhibit metastatic dissemination in preclinical tumor models.¹⁶¹ However, emerging evidence cautions against unregulated TI activation, as maladaptive epigenetic reprogramming may fuel inflammatory pathology. Monocytes primed with LPS exhibit elevated H3K4me1 levels linked to exacerbated post-stroke inflammation, a process mitigated by mesenchymal stem cell therapy.¹⁶² Furthermore, the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) enhances glycolytic flux via endoplasmic reticulum (ER) stress and ROS) signaling, exacerbating systemic inflammation.¹⁶³ TI dysregulation further contributes to chronic inflammatory diseases; in periodontitis and arthritis models, epigenetically driven myeloid cell differentiation sustains tissue destruction.¹⁶⁴ These findings underscore TI’s context-dependent duality, wherein balanced activation enhances defense, whereas excessive engagement fuels pathogenesis.

Mechanistically, TI is categorized into central and peripheral subtypes. Central TI arises from epigenetic reprogramming of hematopoietic progenitors in the bone marrow or thymus, conferring enduring immune memory lasting months to years. Peripheral TI involves transient metabolic-epigenetic adaptations (weeks to months) in tissue-resident immune cells at sites of infection or injury.^165,166 Current TI inducers under investigation include LPS, β-glucan, and vaccines like Bacillus Calmette-Guérin (BCG).^167,168 LPS, a prototypical TLR4 agonist, is a widely studied TI inducer but risks immune tolerance or chronic inflammation due to hyperactivation.^169–171 Conversely, β-glucan enhances antifungal immunity by modulating dendritic cell (DC) function, though its capacity to maintain memory across heterogeneous microenvironments remains unclear.^172,173 BCG exemplifies a “training vaccine” with clinical promise, yet its mechanistic balance between protective priming and pathological immune hyperreactivity demands resolution.^174–176

The regulatory centrality of PRRs in metabolic-epigenetic crosstalk is increasingly evident. PRR activation acts as a master regulator of immune cell plasticity, coordinating metabolic sensors (eg, mTOR, AMPK) and epigenetic modifiers (eg, HDACs, BET proteins) to establish cellular memory. To translate these insights into therapies, four research imperatives emerge: (1) Elucidating spatiotemporal dynamics of PRR-coupled signaling hubs linking pathogen sensing to chromatin accessibility and metabolic shifts; (2) Systematically defining tissue- and disease-specific modifiers (eg, hypoxia, microbiota metabolites) dictating TI outcomes; (3) Designing context-sensitive PRR modulators to balance glycolysis-TCA cycle flux without inducing metabolic exhaustion; (4) Longitudinal profiling of PRR-driven TI in chronic inflammation and aging to resolve its dual roles as protector and disease accelerator. In conclusion, TI redefines immune memory paradigms, transcending classical adaptive immunity frameworks. While PRR-targeted metabolic-epigenetic modulation offers therapeutic promise, maintaining long-term immune homeostasis remains paramount. Future research must prioritize precision platforms that reconcile the pleiotropic effects of PRR signaling across diverse pathological landscapes.

Abbreviations

PRRs, Pattern recognition receptors; TI, Trained immunity; TLRs, Toll-like receptors; CLRs, C-type lectin receptors; MAPK, Mitogen-Activated Protein Kinase; MyD88, Myeloid Differentiation Primary Response 88; TIR, Toll/Interleukin-1 Receptor; IRAK4, Interleukin-1 Receptor-Associated Kinase 4; IRAK1, Interleukin-1 Receptor-Associated Kinase 1; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; CARD9, Caspase Recruitment Domain Containing Protein 9; BCL10, B-cell Lymphoma 10; MALT1, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1; TAK1, TGF-beta-activated kinase 1; IκBα, Inhibitor of Nuclear Factor kappa-B alpha; CpG, cytosine-phosphate-guanine; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharide; CTL, cytotoxic T lymphocyte; CpG ODN, CpG oligodeoxynucleotides; NLRs, NOD-like receptors; CRDs, carbohydrate-recognition domains; RLRs, (RIG-I)-like receptors; MAVS, mitochondrial antiviral-signaling protein; DNMTs, DNA methyltransferases; HDAC, histone deacetylase; miRNAs, microRNAs; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; IRG1, immune-responsive gene 1; TAMs, tumor-associated macrophages; TET2, Tet methylcytosine dioxygenase 2; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PI3K, Phosphoinositide 3-kinase; AKT, Protein kinase B; JAK, Janus kinase; STAT, Signal Transducer and Activator of Transcription; NLRP3, NOD-like receptor family pyrin domain containing 3; JNK1, c-Jun N-terminal kinase 1; BRCC3, BRCA1-Associated Protein 1; AMPK, AMP-activated protein kinase; mTOR, Mammalian Target of Rapamycin; APC, Antigen-Presenting Cell; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; CH25H, cholesterol-25-hydroxylase; 25HC, 25-hydroxycholesterol; PKM2, Pyruvate Kinase M2; TME, tumor microenvironment; TILs, tumor-infiltrating T cells; NAD⁺, Nicotinamide Adenine Dinucleotide; NADH, Nicotinamide Adenine Dinucleotide + Hydrogen; ACC, acetyl-CoA carboxylase; SCFAs, Short-chain fatty acids; RNPII, PRR signaling activates RNA polymerase II; PRC2, Polycomb repressive complex 2; SAM, S-adenosylmethionine; TCA, tricarboxylic acid; SET7, SET domain-containing protein 7; α-KG, α-ketoglutarate; TMAO, trimethylamine N-oxide; ER, endoplasmic reticulum; BCG, Bacillus Calmette-Guérin; DC, dendritic cell.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

We are particularly grateful to all the people who have given us help on our article.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors acknowledge financial support for the research, authorship, and/or publication of this article. This work was funded by the National Natural Science Foundation of China (Grant No. 82360200), the Provincial Innovation Team for Multidisciplinary Diagnosis and Treatment of Complex Craniomaxillofacial Malformations at the Affiliated Stomatology Hospital of Kunming Medical University (Grant No. 202105AE160004), the Yunnan Provincial Oral Disease Clinical Medical Research Center Scientific Research Fund (Grant No. 2022QN004), and the Yunnan Provincial Department of Science and Technology Kunming Medical Joint Special General Project (Grant No. 202301AY070001-062). Partial support was also provided by the First-Class Discipline Team of Kunming Medical University (Grant No. 2024XKTDTS08).

Disclosure

The authors declare that this research was conducted without any commercial or financial relationships that could be perceived as potential conflicts of interest.

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