Didymin switches M1-like toward M2-like macrophage to ameliorate ulcerative colitis via fatty acid oxidation. (July 2021)

• Record Type: Journal Article
• Authors: Lv, Qi; Xing, Yao; Liu, Yijun; Chen, Qingzhu; Xu, Jingyi; Hu, Lihong; Zhang, Yinan
• Is Part Of: Pharmacological research. Volume 169(2021)
• Publication Date: 2021-07
• Subjects: AAV adeno-associated virus -- Acaa 3-ketoacyl-CoA thiolase -- Acadl long chain acyl-CoA dehydrogenases -- Arg-1 arginase-1 -- BMDMs bone marrow-derived macrophages -- Cpt carnitine palmitoyltransferases -- DAI disease activity index -- DMSO dimethyl sulfoxide -- DSS dextran sulfate sodium -- DTT dithiothreitol -- DAPI 4′, 6-diamidino-2-phenylindole -- ECAR extracellular acidification rate -- Echs enoyl CoA hydratase -- ECL enhanced chemiluminescent -- EDTA ethylenediaminetetraacetic acid -- 2-DG 2-deoxyglucose -- FAO fatty acid oxidation -- FBS fetal bovine serum -- FCCP carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone -- GFP green fluorescent protein -- Glut glucose transporter -- Hadh hydroxyacyl-CoA dehydrogenase -- H&E hematoxylin and eosin -- Hk hexokinase -- IFN-γ interferon γ -- LPS lipopolysaccharide -- M-CSF macrophage colony stimulating factor -- MPO myeloperoxidase -- MTP mitochondrial trifunctional protein -- OCR oxygen consumption rate -- OCT optimal cutting temperature -- OXPHOS oxidative phosphorylation -- Pfk phosphofructokinase -- Pk pyruvate kinase -- PMSF phenylmethanesulfonyl fluoride -- PPP pentose phosphate pathway -- PVDF polyvinylidene fluoride -- TAMs tumor-associated macrophage -- TCA tricarboxylic acid cycle -- TNF-α tumor necrosis factor alpha -- UC ulcerative colitis -- 5-ASA 5-aminosalicylic acid; Didymin -- Ulcerative colitis -- Macrophage polarization -- Fatty acid oxidation; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105613
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Inflammatory response by different polarized macrophages has a critical role in a variety of immunological pathophysiology, such as ulcerative colitis (UC). Herein, targeting the paradigm of macrophage phenotypes by small molecular modulators may influence the disease status. In the present study, we firstly demonstrated that didymin, one of the most abundant flavonoid constituents present in the citrus fruits such as oranges and lemons, remarkably attenuated the clinical symptoms of acute and chronic colitis in mice. Mechanistic studies showed that didymin converted pro-inflammatory M1-like to anti-inflammatory M2-like macrophage phenotype, but did not alter the polarization of M2-like macrophages. Metabolic tracing studies revealed that didymin strengthened fatty acid oxidation rather than glycolysis by inducing Hadhb expression. More importantly, in vivo studies verified that promotion of Hadhb expression resulted in the conversion of M1- toward M2-like macrophages and eventually alleviated colitis. Our data highlights the potential of macrophage paradigm in UC inflammation and put forth the stage for considering didymin as a metabolism regulator in reprogramming macrophage polarization, which may serve as a promising therapeutic approach for treatment of inflammation-associated disorders. Graphical Abstract: ga1