Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment

FASEB J. 2018 May;32(5):2339-2353. doi: 10.1096/fj.201700585R. Epub 2017 Dec 19.


Bioactive sphingolipids are modulators of immune processes and their metabolism is often dysregulated in ulcerative colitis, a major category of inflammatory bowel disease (IBD). While multiple axes of sphingolipid metabolism have been investigated to delineate mechanisms regulating ulcerative colitis, the role of acid ceramidase (AC) in intestinal inflammation is yet to be characterized. Here we demonstrate that AC expression is elevated selectively in the inflammatory infiltrate in human and murine colitis. To probe for mechanistic insight into how AC up-regulation can impact intestinal inflammation, we investigated the selective loss of AC expression in the myeloid population. Using a model of intestinal epithelial injury, we demonstrate that myeloid AC conditional knockout mice exhibit impairment of neutrophil recruitment to the colon mucosa as a result of defective cytokine and chemokine production. Furthermore, the loss of myeloid AC protects from tumor incidence in colitis-associated cancer (CAC) and inhibits the expansion of neutrophils and granulocytic myeloid-derived suppressor cells in the tumor microenvironment. Collectively, our results demonstrate a tissue-specific role for AC in regulating neutrophilic inflammation and cytokine production. We demonstrate novel mechanisms of how granulocytes are recruited to the colon that may have therapeutic potential in intestinal inflammation, IBD, and CAC.-Espaillat, M. P., Snider, A. J., Qiu, Z., Channer, B., Coant, N., Schuchman, E. H., Kew, R. R., Sheridan, B. S., Hannun, Y. A., Obeid, L. M. Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment.

Keywords: IBD; MDSC; colitis-associated cancer; sphingolipids; ulcerative colitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Ceramidase / biosynthesis*
  • Acid Ceramidase / genetics
  • Animals
  • Chemokines / biosynthesis
  • Chemokines / genetics
  • Colitis, Ulcerative / enzymology*
  • Colitis, Ulcerative / genetics
  • Colitis, Ulcerative / pathology
  • Colon / enzymology*
  • Colon / pathology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Myeloid-Derived Suppressor Cells / enzymology
  • Myeloid-Derived Suppressor Cells / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neutrophils / enzymology*
  • Neutrophils / pathology
  • Tumor Microenvironment / genetics
  • Up-Regulation*


  • Chemokines
  • Neoplasm Proteins
  • Acid Ceramidase
  • Asah1 protein, mouse