@article{89a6ddbf0c7743ac828862c942218d13,
title = "Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment",
abstract = "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 neutro-philic 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.",
keywords = "Colitis-associated cancer, IBD, MDSC, Sphingolipids, Ulcerative colitis",
author = "Espaillat, {Mel Pilar} and Snider, {Ashley J.} and Zhijuan Qiu and Breana Channer and Nicolas Coant and Schuchman, {Edward H.} and Kew, {Richard R.} and Sheridan, {Brian S.} and Hannun, {Yusuf A.} and Obeid, {Lina M.}",
note = "Funding Information: This work was supported, in part, by a Merit Review Award 2 I01 BX000156 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service (to L.M.O.); U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant F31 DK105711-01 (to M.P.E.); U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences Grant 9R01GM097741-13A1 (to L.M.O.); and a Research Supplement to Promote Diversity in Health-Related Research (to M.P.E.); NIH National Cancer Institute Grant P01 CA097132 (to Y.A.H., L.M.O., and A.J.S.); Stony Brook UniversityW. Burghardt Turner Graduate Fellowship Award (to M.P.E.) and Undergraduate IMSD-MERGE Program (to B.C.). Edward H. Schuchman is an equity holder and consultant for Plexcera Therapeutics LLC, a company founded to develop acid ceramidase therapies for ceramide diseases. He is also named as an inventor on several acid ceramidase-related patents that have been licensed to Plexcera, and will derive royalty income from them should they be commercialized. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. All other authors declare no conflicts of interest. Funding Information: The authors thank Dr. Vincent W. Yang for his expert advice in clinical gastroenterology and colorectal cancer, and Dr. James B. Bliska for his expert advice in BMDM differentiation and culturing (both from the Stony Brook University School of Medicine). The authors also thank the Sphingolipid Animal Cancer Pathobiology Shared Resource Core (P01 CA097132) for the genetically modified models; the Lip-idomics, Research Histology, and Flow Cytometry facilities at Stony Brook University for the technical and analytical work carried out in support of this manuscript; the Lipidomics Shared Resource at Hollings Cancer Center, Medical University of South Carolina (MUSC; Charleston, SC, USA); and the Lipidomics Core in the MUSC Center of Biomedical Research Excellence in Lipidomics and Pathobiology for providing lipid analyses and LCL385. This work was supported, in part, by a Merit Review Award 2 I01 BX000156 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service (to L.M.O.); U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant F31 DK105711-01 (to M.P.E.); U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences Grant 9R01GM097741-13A1 (to L.M.O.); and a Research Supplement to Promote Diversity in Health-Related Research (to M.P.E.); NIH National Cancer Institute Grant P01 CA097132 (to Y.A.H., L.M.O., and A.J.S.); Stony Brook University W. Burghardt Turner Graduate Fellowship Award (to M.P.E.) and Undergraduate IMSD-MERGE Program (to B.C.). Edward H. Schuchman is an equity holder and consultant for Plexcera Therapeutics LLC, a company founded to develop acid ceramidase therapies for ceramide diseases. He is also named as an inventor on several acid ceramidase–related patents that have been licensed to Plexcera, and will derive royalty income from them should they be commercialized. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. All other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2018 FASEB.",
year = "2018",
month = may,
doi = "10.1096/fj.201700585R",
language = "English (US)",
volume = "32",
pages = "2339--2353",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "5",
}