Fibulin7 C-terminal bioactive peptide regulates metabolic profiling of macrophages during inflammation via integrin α5β1

Inflammation can trigger metabolic changes in monocytes and macrophages. Previous studies have shown that a C-terminal fragment of the adhesion protein Fibulin7 (Fbln7-C) and its bioactive peptide (FC-10) can regulate their migration and inflammatory functions of monocytes and macrophages via integrin α5β1, which is associated with the modulation of metabolic pathways in pathological conditions. This study investigates the possible correlation between FC-10-integrin α5β1-mediated cellular and immuno-metabolic programming in macrophages under inflammation. Our results show that FC-10 promoted the anti-inflammatory state in THP-1 and blood monocyte-derived macrophages stimulated with Lipopolysaccharide (LPS), with higher expression of M2 markers (e.g., CD206, IL-10). Further, liquid chromatography coupled tandem mass spectrometry LC-MS/MS based proteomics, metabolomics, and gene expression studies showed a reduced expression of inflammatory, differentiation, and glycolytic proteins (hexokinase and pyruvate kinase). Conversely, expression of the TCA cycle (citrate synthase) and glutamine metabolism proteins (Glutamate Dehydrogenase (GDH1) and SLC1A5) were elevated in the presence of FC-10, depicting an anti-inflammatory phenotype, compared to the control peptide. Furthermore, blocking integrin α5β1 increased the expression of glycolytic proteins (hexokinase) and decreased the glutamine-metabolism-associated proteins (GDH1). In conclusion, our data suggest that FC-10 can regulate metabolic processes in monocytes and macrophages during inflammation and has potential for anti-inflammatory therapeutics.