Background: Systemic Lupus Erythematosus (SLE) is a prototype interferonopathy characterized by multiple organ damage ¹ . Metabolomic analyses of patient-derived sera indicate distinct metabolic pertubations in oxidative and lipid metabolism ^2,3 . Among innate effectors, monocytes (Mo) are implicated in SLE pathogenesis and also display a perturbed metabolic phenotype ⁴ .

Objectives: Based on previous data indicating a prominent IFNα-gene signature in SLE monocytes even during disease remission ⁵ , we herein sought to delineate the metabolic repercussion of IFNα signaling contributing to SLE autoimmunity.

Methods: Using transcriptomic data, we compared the enriched metabolic categories of IFNα(+) and IFNα(-) SLE-Mo ⁶ . In order to compare metabolic perturbations pertaining to SLE, we performed transcriptomic Gene Set Enrichment Analysis (GSEA) ⁷ from in vitro cultured IFNα-activated Mo. We supplemented the analysis with selective ex vivo biochemical inhibition of the metabolic pathways arising from the GSEA and evaluated the effect on inflammatory markers of healthy IFNα-Mo.

Results: We found a statistically significant enrichment of transcripts associated with glycolytic metabolism and lipid biosynthetic and catabolic processes in both IFNα(+)-SLE Mo and healthy IFNα-Mo, but not in IFNα(-)-SLE Mo, which in turn resembled healthy-Mo. Additionally, transcripts associated with cholesterol biosynthetic processes such PMVK , SQLE , LSS , DHCR7 , and LDLR , MVK , FFT1 were significantly upregulated in IFNα(+)-SLE Mo and healthy IFNα-Mo respectively. In accordance, blockade of either glycolysis with the use of 2-DG hexokinase inhibitor, or mevalonic acid synthesis with the use of fluvastatin, attenuated proinflammatory cytokine secretion (IL6, CXCL10) associated with IFN-response in both IFNα(+)-SLE Mo and healthy IFNα-Mo.

Conclusion: Our results link IFNα mediated metabolic shifts in Mo with corresponding metabolic perturbations found in SLE patient-Mo. Pending further confirmation with targeted metabolomics, these data further rationalize the use of IFN blockade and also suggest the potential use of specific metabolites as novel therapeutic targets in SLE.

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Disclosure of Interests: None declared.