Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Nikoletta Kálmán
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Eva Maria Sturm
Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
Barsha Baisakhi Nayak
Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
Julia Teppan
Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
Viola Bagóné Vántus
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Dominika Kovács
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Lilla Makszin
Institute of Bioanalysis, Medical School, Szentágothai Research Center, University of Pécs, 7622 Pécs, Hungary
Tamás Loránd
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Ferenc Gallyas
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Balázs Radnai
Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, Hungary
Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production and acceleration of glycolysis. Macrophage migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase and enolase), was discovered to regulate M1 polarization. Here, we reveal that KRP-6, a potent and highly selective MIF ketonase inhibitor, reduces MIF-induced human blood eosinophil and neutrophil migration similarly to ISO-1, the most investigated tautomerase inhibitor. We equally discovered that KRP-6 prevents M1 macrophage polarization and reduces ROS production in IFN-γ-treated cells. During metabolic reprogramming, KRP-6 improved mitochondrial bioenergetics by ameliorating basal respiration, ATP production, coupling efficiency and maximal respiration in LPS+IFN-γ-treated cells. KRP-6 also reduced glycolytic flux in M1 macrophages. Moreover, the selective MIF ketonase inhibitor attenuated LPS+IFN-γ-induced downregulation of PARP-1 and PARP-2 mRNA expression. We conclude that KRP-6 represents a promising novel therapeutic compound for autoimmune diseases, which strongly involves M1 macrophage polarization.
