MFSD2A promotes epoxygenation of docosahexaenoic acid in gut endothelium to generate pro-resolving lipid mediators and dampen intestinal inflammation

Purpose: The resolution of inflammation is regulated by mediators derived from ω-3 fatty acids, such as docosahexaenoic acid (DHA), that is transported by the Major Facilitator Superfamily Domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta1,2. We wondered whether MFSD2A modulates the DHA metabolism of gut endothelial cells, eventually promoting the resolution of intestinal inflammation in Inflammatory Bowel Disease (IBD). Methods: Lipidomic analysis3 was performed on mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMEC) isolated from surgical specimens of active, resolving IBD patients and healthy subjects4. Healthy HIMEC were transduced with a lentivirus carrying MFSD2A overexpressing vector (MFSD2A-OE), and characterized in vitro. Adoptive transfer of human circulating endothelial progenitor cells (ECFCs), overexpressing MFSD2A, was performed in CD1 nude colitic mice, along with orally administered DHA. Results: The lipidomic analysis revealed a reduced percentage of pro-resolving metabolites derived from CytochRoma P450 epoxygenation of DHA in the inflamed mucosa, when compared with samples from healthy and resolving. We found that reduced level of epoxygenated DHA-derivatives in active tissues correlated with lower amounts of MFSD2A compared to resolving mucosa. MFSD2A, expressed by gut endothelium, exerted proresolving effects in HIMEC in terms of reduced pro-inflammatory markers and anti-angiogenic functions by producing beneficial epoxygenated DHA-derivatives. Transplantation of MFSD2AOE ECFCs in DHA–fed colitic mice ameliorated intestinal inflammation, through stimulation of epoxygenated DHAderivative release in the inflamed mucosa. MFSD2A pro-resolving effects were completely abolished by CYP inhibitor both in vitro and in vivo, demonstrating that protective functions exerted by MFSD2A depends on epoxygenated metabolites of DHA.Discussion: Our study provides the first evidence of MFSD2Adependent regulation of the pro-resolving DHA CYP450-mediated epoxygenation in the IBD-associated vasculature. Conclusion: Our approach may help a selective cohort of nonresponding patients, with the advantage of avoiding immune suppression and using natural endogenous pathways to resolve inflammation. References 1. Wong BH et al. Mfsd2a is a transporter for the essential omega-3 fatty acid DHA in eye and important for photoreceptor cell development. J Biol Chem 2016) doi:10.1074/jbc. M116.721340 2. Prieto-Sánchez MT et al. Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clin Nutr 2016. doi:10.1016/j. clnu.2016.01.014 3. Maddipati KR et al. Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor. FASEB J 2014; 28: 4835-46. 4. D’Alessio S et al. VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest 2014; 124: 3863-78.