Federica Ungaro1, Carlotta Tacconi2, Luca Massimino3, Paola Antonia Corsetto4, Carmen Correale5, Philippe Fonteyne5, Andrea Piontini1, Valeria Garzarelli5, Francesca Calcaterra6, Silvia Della Bella6, Antonino Spinelli7, Michele Carvello8, Angela Maria Rizzo4, Stefania Vetrano1, Luciana Petti9, Gionata Fiorino5, Federica Furfaro5, Domenico Mavilio6, Krishna Rao Maddipati10, Alberto Malesci11, Laurent Peyrin-Biroulet12, Silvia D'Alessio13, Silvio Danese14. 1. IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy. 2. Institute of Pharmaceutical Sciences, Pharmacogenomics, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland. 3. School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy. 4. Departments of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy. 5. IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 6. Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. 7. Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 8. Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 9. IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. 10. Department of Pathology, Lipdomics Core Facility, Wayne State University, Detroit, Michigan. 11. Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 12. Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, France. 13. IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. Electronic address: silvia.dalessio@hunimed.eu. 14. IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy. Electronic address: sdanese@hotmail.com.
Abstract
BACKGROUND & AIMS: Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation. METHODS: We performed lipidomic and functional analyses of MFSD2A in mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMECs) isolated from surgical specimens from patients with active, resolving UC and healthy individuals without UC (controls). MFSD2A was knocked down in HIMECs with small hairpin RNAs or overexpressed from a lentiviral vector. Human circulating endothelial progenitor cells that overexpress MFSD2A were transferred to CD1 nude mice with dextran sodium sulfate-induced colitis, with or without oral administration of DHA. RESULTS: Colonic biopsies from patients with UC had reduced levels of inflammation-resolving DHA-derived epoxy metabolites compared to healthy colon tissues or tissues with resolution of inflammation. Production of these metabolites by HIMECs required MFSD2A, which is required for DHA retention and metabolism in the gut vasculature. In mice with colitis, transplanted endothelial progenitor cells that overexpressed MFSD2A not only localized to the inflamed mucosa but also restored the ability of the endothelium to resolve intestinal inflammation, compared with mice with colitis that did not receive MFSD2A-overexpressing endothelial progenitors. CONCLUSIONS: Levels of DHA-derived epoxides are lower in colon tissues from patients with UC than healthy and resolving mucosa. Production of these metabolites by gut endothelium requires MFSD2A; endothelial progenitor cells that overexpress MFSD2A reduce colitis in mice. This pathway might be induced to resolve intestinal inflammation in patients with colitis.
BACKGROUND & AIMS: Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation. METHODS: We performed lipidomic and functional analyses of MFSD2A in mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMECs) isolated from surgical specimens from patients with active, resolving UC and healthy individuals without UC (controls). MFSD2A was knocked down in HIMECs with small hairpin RNAs or overexpressed from a lentiviral vector. Human circulating endothelial progenitor cells that overexpress MFSD2A were transferred to CD1 nude mice with dextran sodium sulfate-induced colitis, with or without oral administration of DHA. RESULTS: Colonic biopsies from patients with UC had reduced levels of inflammation-resolving DHA-derived epoxy metabolites compared to healthy colon tissues or tissues with resolution of inflammation. Production of these metabolites by HIMECs required MFSD2A, which is required for DHA retention and metabolism in the gut vasculature. In mice with colitis, transplanted endothelial progenitor cells that overexpressed MFSD2A not only localized to the inflamed mucosa but also restored the ability of the endothelium to resolve intestinal inflammation, compared with mice with colitis that did not receive MFSD2A-overexpressing endothelial progenitors. CONCLUSIONS: Levels of DHA-derived epoxides are lower in colon tissues from patients with UC than healthy and resolving mucosa. Production of these metabolites by gut endothelium requires MFSD2A; endothelial progenitor cells that overexpress MFSD2A reduce colitis in mice. This pathway might be induced to resolve intestinal inflammation in patients with colitis.
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