Transcriptional changes induced in immune cells following PRR stimulation forge the immune response. Several groups have shown that, besides gene transcription, PRR activation also induces profound changes in the metabolism of immune cells that potently affect the final outcome of the immune response. In particular, phagocytes relay primarily on respiration during homeostasis, and

once these cells are activated by microbial ligands, they switch to glycolysis. If and how the coincident recognition of exogenous and endogenous ligands affects the metabolic switch of phagocytes during an immune response was a mystery. We reveal that oxidized endogenous phospholipids not only activate the inflammasome (Science, 2016; Immunity, 2017), but also are able to rewire the metabolism of phagocytes. We initially characterized in vitro the metabolism of macrophages exposed to oxidized endogenous phospholipids and bacterial components. We documented that upon encountering oxidized endogenous phospholipids, phagocytes assume a new metabolic state, in which respiration and glycolysis are both active. This new metabolic state requires the potentiation of mitochondria activity, and allows hyperproduction of the pro-form of interleukin-1β (Nature Immunology, 2020).

We, thus, termed this state “hypermetabolism”. We next focused our attention on a mouse model of atherosclerosis that is driven by accumulation of oxidized phospholipids in the blood. Our data demonstrate that hypermetabolic macrophages potently sustain the development of atherosclerosis, and that pharmacological intervention against the pathways that lead to hypermetabolism significantly decreases inflammation and atherosclerotic plaque formation. These data point to the therapeutic use of applying drugs that inhibit the formation of hypermetabolic macrophages in the context of

cardiovascular disorders, which are a major cause of death in Western countries.

We are currently expanding these studies by using proteomics, metabolomics and transcriptomics and extending the relevance of our findings not only to atherosclerosis, but also to sepsis and colitis.

ZanoniLab

Macrophages and their mitochondria. Red: mitochodria; Blue:cytoskeleton; Cyan: nuclei. Credit to Dr. Di Gioia

Header picture: Macrophages and their organelles: electron microscopy. Credit to Dr. Di Gioia