MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice

Federica Ungaro, Carlotta Tacconi, Luca Massimino, Paola Antonia Corsetto, Carmen Correale, Philippe Fonteyne, Andrea Piontini, Valeria Garzarelli, Francesca Calcaterra, Silvia Della Bella, Antonino Spinelli, Michele Carvello, Angela Maria Rizzo, Stefania Vetrano, Luciana Petti, Gionata Fiorino, Federica Furfaro, Domenico Mavilio, Krishna Rao Maddipati, Alberto MalesciLaurent Peyrin-Biroulet, Silvia D'Alessio, Silvio Danese

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1363-1377.e6
JournalGastroenterology
Volume153
Issue number5
DOIs
Publication statusPublished - Nov 1 2017

Keywords

  • Angiogenesis
  • Gut Vasculature
  • IBD
  • Inflammatory Bowel Disease

ASJC Scopus subject areas

  • Gastroenterology

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