Interplay Between Cellular Metabolism and Epigenetic Reprogramming in the Pathogenesis of Chronic Inflammatory Disorders: A Translational Perspective

Abstract

Chronic inflammatory diseases (CIDs), such as rheumatoid arthritis (RA), inflammatory bowel disease, systemic lupus erythematosus and psoriasis represents an enormous global health challenge due to their chronic relapsing-remitting course, high morbidity and lack of therapeutic armament. Although classically viewed as effects of immune deregulation, recent observations reveal a more complex pathogenic scenario involving the crosstalk between cellular metabolism and epigenetic remodeling. The metabolic intermediates including acetyl-CoA, α-ketoglutarate, lactate and NAD⁺ not only provide energy supply for the cell but also serve as cofactors for and activators of chromatin-modifying enzymes, connecting bioenergetic status with transcriptional regulation. This reciprocal connection forms a self-propagating feedback loop in immune cells to drive pathological phenotypes and sustain chronic inflammation.
Recent evidence indicates that effector T cells and pro-inflammatory macrophages are highly dependent on glycolysis, in contrast to regulatory T cells and anti-inflammatory macrophages which mainly utilize oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Such different metabolic requirements mold into epigenetic landscapes with the consequences of being involved in DNA methylation, histone modifications and non-coding RNAs that can ultimately direct pro-inflammatory or tolerogenic programs. Reversed epigenetic memory also adds to the persistence and relapse of abnormal disease.
Clinically, metabolic (e.g., glycolysis inhibitors, AMPK inducers) or epigenetic modifiers (e.g., HDAC, DNMT and BET inhibitors) could restore the immune homoeostasis. Dual approaches targeting metabolic and genetic-epigenetic pathways concurrently may have a synergistic impact, but it will be important to address specificity, toxicity, and heterogeneity of the patient population. Future with single cell multi-omics, precision medicine and integrative modeling Technologically sophisticated developments are necessary to translate pre-clinical results into clinic.
In this review, we amalgamate the recent advances in metabolism–epigenetics axis in CIDs, introducing new mechanistic understanding of immune cell reprogramming and describing potential therapeutic strategies as well as knowledge gaps. Insight into this interaction is the basis for novel, mechanism-based therapies directed at achieving prolonged disease control.

Keywords:

Cellular Metabolism, Epigenetic Reprogramming, Chronic Inflammatory Disorders (CIDs), Immune Cell Plasticity, Metabolism–Epigenetics Crosstalk, Translational Therapeutics

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