Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability

Ye Ryung Kim, Giora Volpert, Kyong Oh Shin, So Yeon Kim, Sun Hye Shin, Younghay Lee, Sun Hee Sung, Yong Moon Lee, Jung Hyuck Ahn, Yael Pewzner-Jung, Woo Jae Park, Anthony H. Futerman, Joo Won Park

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long-chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very-long acyl chain ceramides with concomitant increase of long chain bases and C16-ceramides, were more susceptible to dextran sodium sulphate-induced colitis, and their survival rate was markedly decreased compared with that of wild-type littermates. Using mixed bone-marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule-A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco-2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2-knockdown via CRISPR-Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long-chain bases and C16-ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC-dextran levels, indicating that altered SLs including deficiency of very-long-chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.

Original languageEnglish
Pages (from-to)3565-3578
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume21
Issue number12
DOIs
StatePublished - Dec 2017

Keywords

  • acyl chains
  • ceramide
  • dextran sodium sulphate
  • inflammatory bowel disease
  • sphingolipid

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