Immunometabolism of monocyte/macrophage system in chronic diseases

In recent years, immunometabolism has emerged as a key field to understand the interplay between cellular metabolism and immune cell function, offering novel therapeutic perspectives in chronic inflammatory diseases. Therefore, we explored the role of immunometabolic reprogramming, particularly within the monocyte/macrophage system, in two major pathologies: Alzheimer’s disease (AD) and metabolic dysfunction-associated steatohepatitis (MASH). In the context of AD, the key-role of microglia, brain-resident macrophages, as major pathogenic drivers, has recently emerged. Amyloid beta peptide (Aβ) and circulating lipopolysaccharide (LPS) activates microglia via toll-like receptor (TLRs), promoting cytokine production. We investigated the role of metabolic modulation in the control of inflammatory activity in HMC3 line, activated by LPS exposure simultaneously treated with dimethyl malonate (DMM), a succinate dehydrogenase (SDH) inhibitor. Analysing cellular bioenergetics and biochemical alterations in HCM3, we demonstrated that LPS induced a metabolic rewiring characterised by high glycolysis and mitochondrial respiration with high reactive oxygen species (ROS) generation. DMM partially restored normal functions by inhibiting SDH but also by limiting the LPS-induced mitochondrial biogenesis. We also underlined a possible role of hypoxia inducible-factor 1 α (HIF- 1α). A hyper bioenergetic profile was also detected in microglia isolated from 3xTg-AD mice, and DMM in vivo administration revealed a potential strategy to control microglia metabolic reprogramming, dampening inflammation in the early stages of disease. In MASH, we revealed a distinct bioenergetic profile in circulating monocytes from patients, characterized by elevated glycolysis and enhanced mitochondrial respiration, particularly at the level of SDH (Complex II). This metabolic shift leads to excessive ROS production and is transcriptionally sustained via the AMPK-mTOR-PGC-1α axis. The inhibition of SDH with DMM successfully rebalanced mitochondrial activity, reduced pro-inflammatory cytokine production, and restored cellular metabolic homeostasis. Moreover, scRNA-seq data from murine models confirmed that monocyte-derived hepatic macrophages in MASH exhibit upregulation of both mitochondrial and glycolytic energy pathways. In vivo, DMM administration effectively reduced liver macrophage infiltration and inflammation. Interestingly, these results highlight the role of metabolic reprogramming as a driver of chronic inflammation, suggesting immunometabolism as a potential target in both AD and MASH.