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

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: epigenetic; immunocyte; metabolic reprogramming; pattern recognition receptors; trained immunity.

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).

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).

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).