Monocyte reprogramming and trained immunity: Linking metabolism to inflammation in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents a global clinical challenge, largely due to the liver’s central role as a key immunometabolic organ. Recent research underscores the systemic immunometabolic nature of NAFLD. It has been shown that peripheral blood immune cells of NAFLD patients exist in a primed state, which aligns with the concept of long-term functional reprogramming of innate immune cells in metabolic diseases. This functional reprogramming - encompassing priming and trained immunity - represents a recently described facet of innate immunity. While evolutionarily beneficial for host defense, these mechanisms are now recognized as contributors to the pathogenesis of various chronic non-communicable diseases. It is hypothesized that monocyte reprogramming, induced by chronic exposure to metabolic signals such as lipotoxicity and hyperglycemia, fosters a hyperactive pro-inflammatory phenotype. This phenotype significantly contributes to disease pathogenesis and the development of systemic immunometabolic disturbances. Understanding the role of immunometabolic reprogramming opens new prospects for the search of biomarkers and the development of therapeutic strategies aimed at modulating the metabolism of immune cells in NAFLD.

Keywords: Non-alcoholic fatty liver disease; Innate immune system; Immunometabolism; Metabolic reprogramming; Priming; Trained immunity; Monocytes

Core Tip: Non-alcoholic fatty liver disease is a systemic immunometabolic disorder. Chronic exposure to metabolic factors such as lipotoxicity and hyperglycemia induces long-term functional reprogramming of innate immunity, underlying phenomena like priming and trained immunity. The resulting hyperactive pro-inflammatory phenotype of monocytes and macrophages serves as a key mechanism linking obesity, insulin resistance, and chronic liver inflammation, opening new avenues for therapeutic intervention.