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

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

doi:10.1053/j.gastro.2017.07.048

Cited by 48 publications

(44 citation statements)

References 62 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the endogenous production of 17-HDHA was significantly reduced in leukocytes from obese individuals, an impairment that was also observed when these leukocytes were incubated with exogenous concentrations of DHA. This finding could be caused by a reduced uptake of DHA because in obese leukocytes, we found a remarkable decrease in the protein levels of the membrane transporter MFSD2A required for the cellular incorporation of DHA (16,28). However, the observation that only 17-HDHA (derived from DHA through the activity of 15-LOX) was significantly reduced in obese leukocytes in the absence of changes in other monohydroxy fatty acids, including 14-HDHA, 13-HDHA, 7-HDHA and 4-HDHA derived from DHA suggests compromised 15-LOX activity in this condition.…”

Section: Discussionmentioning

confidence: 84%

Leukocytes from obese individuals exhibit an impaired SPM signature

et al. 2019

View full text Add to dashboard Cite

Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low‐grade systemic inflammation showed reduced leukocyte production of the DHA‐derived monohydroxy fatty acid 17—hydroxy‐DHA (HDHA) and unbalanced formation of SPMs (in particular d‐series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15‐lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5‐LOX levels and reduced 5‐LOX Ser271 phosphorylation and distinct intracellular 5‐LOX redistribution. However, 15‐LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of d‐series Rvs was completely rescued by incubation with the intermediate precursor 17‐HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17‐HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.—López‐Vicario, C, Titos, E., Walker, M. E., Alcaraz‐Quiles, J., Casulleras, M., Durán‐Güell, M., Flores‐Costa, R., Pérez‐Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 33, 7072–7083 (2019). http://www.fasebj.org

show abstract

Section: Discussionmentioning

confidence: 84%

Leukocytes from obese individuals exhibit an impaired SPM signature

et al. 2019

View full text Add to dashboard Cite

show abstract

“…At 24 h after ACC, our microarrays analyses suggested reduced Mfsd2a levels in spinal cord of WT ACC-Non-P mice as compared with WT sham mice (data not shown). Given that: (i) Mfsd2a is required for the integrity and function of BBB [5]; (ii) Mfsd2a transports DHA to the brain [6];(iii) The anti-inflammatory Neuroprotectin-D1, known to protect brain and retina against cell injury-induced oxidative stress [22], is produced from DHA; (iv) endothelial cells that overexpress Mfsd2a reduce colitis in mice by generating inflammation-resolving lipid mediators [23]; and(v) The 3′-untranslated region of Mfsd2a transcripts contains a miR-155 target site (www.targetscan.org), we hypothesized that targeting of Mfsd2a by miR-155 may impair termination of inflammatory response and consequently increase CCE and ischemic damage to the spinal cord.…”

Section: Resultsmentioning

confidence: 99%

“…Also, given that anti-inflammatory Neuroprotectin-D1, that protects brain and retina against cell injury-induced oxidative stress [22], is produced from DHA in the brain, it is likely that reduced DHA supply should translate into higher, prolonged inflammatory response to ischemia. Specifically, a recent report showed that Mfsd2a promotes endothelial generation of inflammation-resolving lipid mediators and reduces colitis [23], a pathology tightly linked to intestinal barrier malfunction and high levels of miR-155 [34]. Thus, Mfsd2a allows to mount a proper anti-in-flammatory response in intestinal vasculature, and accordingly MFSD2A is higher in patients with ulcerative colitis undergoing remission [23].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, a recent report showed that Mfsd2a promotes endothelial generation of inflammation-resolving lipid mediators and reduces colitis [23], a pathology tightly linked to intestinal barrier malfunction and high levels of miR-155 [34]. Thus, Mfsd2a allows to mount a proper anti-in-flammatory response in intestinal vasculature, and accordingly MFSD2A is higher in patients with ulcerative colitis undergoing remission [23]. This results are strikingly similar to our own results showing that WT ACC-NP mice have higher Mfsd2a expression in spinal cord compare to sham or paralyzed mice, further substantiating our hypothesis of Mfsd2a being protective and miR-155 being deleterious in ischemic spinal cords.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

MiR-155 deletion reduces ischemia-induced paralysis in an aortic aneurysm repair mouse model: Utility of immunohistochemistry and histopathology in understanding etiology of spinal cord paralysis

Awad

Bratasz

Nuovo

et al. 2018

Annals of Diagnostic Pathology

View full text Add to dashboard Cite

Spinal cord paralysis is relatively common after surgical repair of thoraco-abdominal aortic aneurysm (TAAA) and its etiology is unknown. The present study was designed to examine the histopathology of the disease and investigate whether miR-155 ablation would reduce spinal cord ischemic damage and delayed hindlimb paralysis induced by aortic cross-clamping (ACC) in our mouse model. The loss of locomotor function in ACC-paralyzed mice correlated with the presence of extensive gray matter damage and central cord edema, with minimal white matter histopathology. qRTPCR and Western blotting showed that the spinal cords of wild-type ACC mice that escaped paralysis showed lower miR-155 expression and higher levels of transcripts encoding Mfsd2a, which is implicated in the maintenance of blood-brain barrier integrity. In situ based testing demonstrated that increased miR-155 detection in neurons was highly correlated with the gray matter damage and the loss of one of its targets, Mfsd2a, could serve as a good biomarker of the endothelial cell damage. In vitro, we demonstrated that miR-155 targeted Mfsd2a in endothelial cells and motoneurons and increased endothelial cell permeability. Finally, miR-155 ablation slowed the progression of central cord edema, and reduced the incidence of paralysis by 40%. In sum, the surgical pathology findings clearly indicated that the epicenter of the ischemic-induced paralysis was the gray matter and that endothelial cell damage correlated to Mfsd2a loss is a good biomarker of the disease. MiR-155 targeting therefore offers new therapeutic opportunity for edema caused by traumatic spinal cord injury and diagnostic pathologists, by using immunohistochemistry, can clarify if this mechanism also is important in other ischemic diseases of the CNS, including stroke.

show abstract

“…IBD patients were diagnosed by physicians based on clinical, endoscopic and histological criteria. Endoscopic activities were assessed using the endoscopic Mayo score 49 , and the Riley histological scoring system 50 as described in Ungaro et al., 2017 51 Healthy colonic biopsies were obtained from patients undergoing routine check-up for non-IBD related diseases. For patients' characteristics see the Supplementary Table 1.…”

Section: Collection Of Human Biopsies For Viral Amplicon Detection Afmentioning

confidence: 99%

Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease

et al. 2018

Self Cite

View full text Add to dashboard Cite

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

Abstract: Abstract:Background & Aims: Alterations in signaling pathways that regulate resolution of

Cited by 48 publications

References 62 publications

Leukocytes from obese individuals exhibit an impaired SPM signature

Leukocytes from obese individuals exhibit an impaired SPM signature

MiR-155 deletion reduces ischemia-induced paralysis in an aortic aneurysm repair mouse model: Utility of immunohistochemistry and histopathology in understanding etiology of spinal cord paralysis

Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease

Contact Info

Product

Resources

About