Lipid deprivation amplifies type I IFN responses in monocytes through prenylation: insights from familial combined hypolipidemia type 2.

Familial Combined Hypolipidemia (FHBL2) is a genetic disorder caused by loss-of-function mutations in the Angiopoietin-like 3 (ANGPTL3) gene. FHBL2 subjects exhibit hypolipidemia and protection from atherosclerotic cardiovascular diseases. Here, we explored the hypothesis that immunometabolic events contribute to this atheroprotective phenotype. To this aim, circulating monocytes from FHBL2 subjects and controls were profiled through gene expression and phenotypic analysis in vivo and ex vivo. In parallel, immune responses were analyzed in monocytes that were lipid-deprived in vitro. In FHBL2 subjects, leukocytes exhibited lower content of intracellular lipids, together with a spontaneous type I IFN signature in vivo and higher sensitivity to IFN stimulation ex vivo. Lipid restriction in vitro was sufficient to recapitulate the higher IFN sensitivity in monocytes, while activating the mevalonate and isoprenoid synthetic pathway. These two events were linked, since a prenylation inhibitor reverted the high IFN response under lipid deprivation. Finally, we found that lipid restriction repressed, in a prenylation- and IFN-dependent fashion, the production of the inflammatory and proatherogenic cytokine IL-1β, and suppressed mitochondrial metabolism, which is a known trigger for inflammasome activation. In summary, we uncovered a novel immunometabolic mechanism linking lipid deprivation in monocytes, isoprenoid synthesis, enhanced IFN response, and IL-1β control. This circuit may provide an immunometabolic basis for the protection from atherosclerotic diseases in hypolipidemic subjects.