Regulation of immune cell metabolism by therapeutic normal IgG intravenous immunoglobulin.

Abstract

Immune cell metabolism and metabolic end products influence the nature and magnitude of immune responses. Various autoimmune and inflammatory diseases are associated with dysregulated cellular metabolism. Intravenous immunoglobulin (IVIG), a therapeutic pooled normal IgG, is extensively used for the immunotherapy of a wide range of autoimmune and inflammatory diseases. Although several cellular and molecular mechanisms of action of IVIG have been reported, the role of IVIG in modulating the immune cell metabolism remains unknown. We sought to investigate the influence of IVIG on the metabolic events of human immune cells. We performed metabolic flux analyses on inflammatory mediators-stimulated human PBMCs. Furthermore, intracellular metabolites were extracted from activated PBMCs and subjected to liquid chromatography coupled to high-resolution mass spectrometry. Untargeted global metabolic profiling of PBMCs was performed to determine the metabolic landscape of immune cells and metabolic reprogramming by IVIG. Untargeted lipidomics was used for the mechanistic studies on IVIG-induced lipogenesis. IVIG and its Fc and F(ab')₂ fragments regulate the Warburg effect in activated PBMCs depending on the glucose availability. Untargeted global metabolic profiling revealed that IVIG alters the overall metabolic landscape of inflammatory mediators-stimulated PBMCs, blocks prenylation of amino acid cysteine, and promotes lipogenesis of well-known anti-inflammatory lipids such as diacylglycerol and triacylglycerol by shuttling acetyl coenzyme A away from the mevalonate pathway. Mechanistically, IVIG-induced lipogenesis was mediated via F(ab')₂ fragments and was dependent on the sialylated glycans of IgG. Our data indicate that IVIG targets immune cell metabolism and also highlight a novel mechanism of action of IVIG in the context of immunotherapy of autoimmune and inflammatory diseases.