Lipid restriction amplifies type I interferon response in monocytes: lessons learnt from familial hypolipidemia

Monocytes are members of the mononuclear phagocyte system (MPS) together with macrophages and dendritic cells. They play a key role in health and in disease. In particular they play beneficial or detrimental functions in hyperlipidemia and cardiovascular disease. Cells functions are deeply influenced by systemic and intracellular metabolism. Although much is known about the metabolism of immune cells, the effect of systemic and intracellular metabolism on immune cell function has not been deeply investigated. FHBL2 subjects are protected against cardiovascular disease, and they represent a unique contest to study and understand how systemic metabolism influences intracellular innate immune cells metabolism. We performed ex vivo analysis of FHBL2 subjects and controls and we observed that monocytes of FHBL2 subjects display lower intracellular lipid content and higher sensitivity to type I IFN compared to control groups. We developed an in vitro system that resemble the phenotype observed ex vivo: we cultured monocytes in normal serum, lipid deprived serum and lipid deprived serum plus LDL. We took advantage of this system to dissect the metabolic mechanism behind the unique profile we observed in FHBL2 subjects. This system allow us to study all the major metabolic pathways. We observed that lipid deprivation reduced mitochondrial fitness and glycolytic metabolism, and interestingly, we found reduced ER stress response in lipid deprived condition compared to normal serum condition. Then we assessed if lipid deprived serum induces a spontaneous type I IFN production. By quantitative Real Time PCR we analyzed the expression of IRF3 in enriched monocytes cultured in different lipid conditions and we noticed a slightly higher expression of IRF3 in lipid deprived serum compared to normal serum condition. Since type I IFN production is strongly related to the mevalonate pathway activity, we performed a quantitative Real Time PCR of the most representative genes of the mevalonate pathway in enriched monocytes cultured in different lipid conditions. We found that the mevalonate pathway is induced in lipid restricted condition and that protein prenylation sustain the higher type I IFN responsiveness that we observed in lipid deprived setting. Finally, we performed a functional analysis of enriched monocytes cultured in different lipid conditions. In lipid deprived condition we observed a specific IL-1b suppression mediated by the protein prenylation and by type I IFN. Hypolipidemia establishes a peculiar immune profile, characterized by a shift from inflammasome to IFN response which contributes to protect FHBL2 subjects to cardiovascular disease.