Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming
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 tautomer...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/10/1790 |
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| author | Eszter Vámos Nikoletta Kálmán Eva Maria Sturm Barsha Baisakhi Nayak Julia Teppan Viola Bagóné Vántus Dominika Kovács Lilla Makszin Tamás Loránd Ferenc Gallyas Balázs Radnai |
| author_facet | Eszter Vámos Nikoletta Kálmán Eva Maria Sturm Barsha Baisakhi Nayak Julia Teppan Viola Bagóné Vántus Dominika Kovács Lilla Makszin Tamás Loránd Ferenc Gallyas Balázs Radnai |
| author_sort | Eszter Vámos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:29:43Z |
| format | Article |
| id | doaj.art-c0c9d5b9aad4471c81497d27643fe5b2 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T21:29:43Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-c0c9d5b9aad4471c81497d27643fe5b22023-11-19T15:27:12ZengMDPI AGAntioxidants2076-39212023-09-011210179010.3390/antiox12101790Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic ReprogrammingEszter Vámos0Nikoletta Kálmán1Eva Maria Sturm2Barsha Baisakhi Nayak3Julia Teppan4Viola Bagóné Vántus5Dominika Kovács6Lilla Makszin7Tamás Loránd8Ferenc Gallyas9Balázs Radnai10Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryInstitute of Bioanalysis, Medical School, Szentágothai Research Center, University of Pécs, 7622 Pécs, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, 12 Szigeti Str., 7624 Pécs, HungaryMacrophage 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.https://www.mdpi.com/2076-3921/12/10/1790macrophage polarizationmetabolic reprogrammingglycolysisoxidative phosphorylationMIFMIF inhibitor |
| spellingShingle | Eszter Vámos Nikoletta Kálmán Eva Maria Sturm Barsha Baisakhi Nayak Julia Teppan Viola Bagóné Vántus Dominika Kovács Lilla Makszin Tamás Loránd Ferenc Gallyas Balázs Radnai Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming Antioxidants macrophage polarization metabolic reprogramming glycolysis oxidative phosphorylation MIF MIF inhibitor |
| title | Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming |
| title_full | Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming |
| title_fullStr | Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming |
| title_full_unstemmed | Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming |
| title_short | Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming |
| title_sort | highly selective mif ketonase inhibitor krp 6 diminishes m1 macrophage polarization and metabolic reprogramming |
| topic | macrophage polarization metabolic reprogramming glycolysis oxidative phosphorylation MIF MIF inhibitor |
| url | https://www.mdpi.com/2076-3921/12/10/1790 |
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