Modulation of the energy metabolism inhibits plasmacytoid dendritic cell activation and delays onset of autoantibody production in murine models of systemic lupus erythematosus

Abstract

Abstract Despite the heterogeneity of systemic lupus erythematosus (SLE) clinical manifestations, an increased expression of type I interferon (IFN) regulated genes, termed the interferon signature, has been reported in most SLE patients. Long recognized to facilitate the progression of SLE, Type I IFNs can be produced in small amounts by most cell types, but the plasmacytoid dendritic cells (pDCs) are the primary producers. Since murine models of SLE have shown that depletion of pDCs stop the onset and progression of autoimmunity, we speculated that it is important to suppress pDC activities that go beyond the production of type I IFNs. We have confirmed that changes in fatty acid metabolism are essential for pDC activation. Using inhibitors of fatty acid oxidation, oxidative phosphorylation, and glycolysis, we have found that metabolic modulation prevents pDC activation upon stimulation with TLR ligands CpG and R848. This metabolic inhibition did not affect pDC viability. Moreover, in vivo treatment of mice with metabolic inhibitors delayed the onset of autoantibody production in murine models of SLE. Indeed, the inhibition of energy metabolism strongly reduced the production of anti-dsDNA and antichromatin autoanti-bodies in i) a model of lupus induced by Graft versus Host Disease (GvHD) and ii) in lupus-prone mice accelerated by TLR stimulation. Therefore, our findings suggest that the in vivo suppression of the major producers of type I IFN through inhibition of energy metabolism may therapeutically downregulate the production of autoantibodies in murine lupus. Our data raises the possibility of manipulating cellular metabolic pathways to regulate the detrimental type I IFN effects in SLE.