Journal Article

MIF tautomerase inhibitor TE-11 prevents inflammatory macrophage activation and glycolytic reprogramming while reducing leukocyte migration and improving Crohn’s disease-like colitis in male mice

Deák, Péter, Gallyas, Ferenc Jr, Radnai, Balázs, Nayak, Barsha Baisakhi, Makszin, Lilla, Vámos, Eszter, Vántus, Viola Bagóné, Kálmán, Nikoletta, Loránd, Tamás, Sturm, Eva Maria

2025

Overview

Crohn's disease (CD) is a chronic inflammatory disorder primarily affecting the gastrointestinal tract. Leukocyte recruitment, M1 macrophage polarization and associated metabolic reprogramming are hallmarks of its pathomechanism. Here, we tested TE-11, a potent MIF tautomerase inhibitor (IC = 5.63 μmol/dm ) in experimental Crohn's disease in male mice, in leukocyte recruitment and in inflammatory M1 macrophage activation. 2,4,6-trinitrobenzenesulfonic acid-(TNBS)-induced colitis was utilized as a CD-model in male mice. We performed macroscopic scoring and cytokine measurements. We also analyzed MIF-induced leukocyte migration and evaluated apoptosis. LPS+IFN-γ-induced RAW264.7 cells were applied as a M1 macrophage model. We performed qPCR, ROS and nitrite determinations, ELISA measurements, mitochondrial oxygen consumption rate and extracellular acidification rate determinations. TE-11 improved mucosal damage, reduced inflammation score and concentration of IL-1β and IL-6 in the colon. It inhibited MIF-induced human blood eosinophil and neutrophil migration and counteracted the anti-apoptotic effect of MIF. In macrophages, MIF inhibition prevented M1 polarization by downregulating HIF-1α gene expression in LPS+IFN-γ-activated cells. Additionally, the molecule reduced mRNA transcription and protein expression of chemokine CCL-2 and cytokine IL-6 while further increasing SOD2 gene transcription and decreased ROS and nitrite production in macrophages. During inflammatory metabolic reprogramming, TE-11 prevented LPS+IFN-γ-induced metabolic shift from OXPHOS to glycolysis. Similarly to anti-inflammatory M2 cells, TE-11 improved mitochondrial energy production by increasing basal respiration, ATP production, coupling efficiency, maximal respiration and spare respiratory capacity. Comprehensively, TE-11, a MIF tautomerase inhibitor ameliorates CD-like colitis, reduces MIF-induced eosinophil and neutrophil migration and prevents M1 polarization and associated metabolic reprogramming; therefore, it may prove beneficial as a potential drug candidate regarding CD therapy.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acidification / Animals / Apoptosis / Cell activation / Cell Movement - drug effects / Chemokines / Colitis / Colitis - chemically induced / Colitis - drug therapy / Colitis - immunology / Colitis - metabolism / Colon / Crohn Disease - drug therapy / Crohn Disease - immunology / Crohn Disease - metabolism / Crohn Disease - pathology / Crohn's disease / Cytokines / Dehydrogenases / Disease Models, Animal / Drug development / Electron transport / Enzymes / Experiments / Flow cytometry / Gastrointestinal tract / Gene expression / Glycolysis / Glycolysis - drug effects / Granulocytes / Humans / Hypoxia-inducible factor 1a / Immunology / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Interleukin 6 / Intramolecular Oxidoreductases - antagonists & inhibitors / Intramolecular Oxidoreductases - metabolism / Leukocyte migration / Leukocytes / Leukocytes (eosinophilic) / Leukocytes (neutrophilic) / Lipopolysaccharides / M1 polarization / macrophage activation / Macrophage Activation - drug effects / Macrophage Migration-Inhibitory Factors - antagonists & inhibitors / Macrophage Migration-Inhibitory Factors - metabolism / Macrophages / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Male / metabolic reprogramming / Metabolism / Mice / Microorganisms / MIF / MnSOD gene / Neutrophils / Oxidation / Oxygen consumption / Polarization / RAW 264.7 Cells / γ-Interferon