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

14 Citations (Scopus)

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

Fingerprint

Colitis
Docosahexaenoic Acids
Ulcerative Colitis
Inflammation
Lipids
Endothelial Cells
Endothelium
Colon
Mucous Membrane
Biopsy
Epoxy Compounds
Dextrans
Lipid Metabolism
Nude Mice
Placenta
Small Interfering RNA
Oral Administration
Retina
Sodium
Brain

Keywords

  • Angiogenesis
  • Gut Vasculature
  • IBD
  • Inflammatory Bowel Disease

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{fb27341b84f143028e326c72f7825e0a,
title = "MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice",
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.",
keywords = "Angiogenesis, Gut Vasculature, IBD, Inflammatory Bowel Disease",
author = "Federica Ungaro and Carlotta Tacconi and Luca Massimino and Corsetto, {Paola Antonia} and Carmen Correale and Philippe Fonteyne and Andrea Piontini and Valeria Garzarelli and Francesca Calcaterra and {Della Bella}, Silvia and Antonino Spinelli and Michele Carvello and Rizzo, {Angela Maria} and Stefania Vetrano and Luciana Petti and Gionata Fiorino and Federica Furfaro and Domenico Mavilio and Maddipati, {Krishna Rao} and Alberto Malesci and Laurent Peyrin-Biroulet and Silvia D'Alessio and Silvio Danese",
year = "2017",
month = "11",
day = "1",
doi = "10.1053/j.gastro.2017.07.048",
language = "English",
volume = "153",
pages = "1363--1377.e6",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",

}

TY - JOUR

T1 - MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice

AU - Ungaro, Federica

AU - Tacconi, Carlotta

AU - Massimino, Luca

AU - Corsetto, Paola Antonia

AU - Correale, Carmen

AU - Fonteyne, Philippe

AU - Piontini, Andrea

AU - Garzarelli, Valeria

AU - Calcaterra, Francesca

AU - Della Bella, Silvia

AU - Spinelli, Antonino

AU - Carvello, Michele

AU - Rizzo, Angela Maria

AU - Vetrano, Stefania

AU - Petti, Luciana

AU - Fiorino, Gionata

AU - Furfaro, Federica

AU - Mavilio, Domenico

AU - Maddipati, Krishna Rao

AU - Malesci, Alberto

AU - Peyrin-Biroulet, Laurent

AU - D'Alessio, Silvia

AU - Danese, Silvio

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Gut Vasculature

KW - IBD

KW - Inflammatory Bowel Disease

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U2 - 10.1053/j.gastro.2017.07.048

DO - 10.1053/j.gastro.2017.07.048

M3 - Article

C2 - 28827082

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VL - 153

SP - 1363-1377.e6

JO - Gastroenterology

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