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SHR Neuro Cancer Cardio Lipid Metab Microb

Vámos, E; Vántus, VB; Deák, P; Kálmán, N; Sturm, EM; Nayak, BB; Makszin, L; Loránd, T; Gallyas, F Jr; Radnai, B.
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
FRONT IMMUNOL. 2025; 16: 1558079 Doi: 10.3389/fimmu.2025.1558079 [OPEN ACCESS]
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Leading authors Med Uni Graz: Radnai Balazs
Co-authors Med Uni Graz: Böhm Eva; Nayak Barsha Baisakhi
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Abstract:: Background & aims 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 (IC50 = 5.63 mu mol/dm3) in experimental Crohn's disease in male mice, in leukocyte recruitment and in inflammatory M1 macrophage activation.Methods 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-gamma-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.Results TE-11 improved mucosal damage, reduced inflammation score and concentration of IL-1 beta 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-1 alpha gene expression in LPS+IFN-gamma-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-gamma-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.Conclusion 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.
Find related publications in this database (Keywords): Crohn's disease; MIF; macrophage activation; M1 polarization; metabolic reprogramming