Loss of Acid Ceramidase in Myeloid Cells Protects From Chronic Colitis in IL10-Deficient Mice.

Patients with inflammatory bowel disease exhibit elevated expression of acid ceramidase (AC), an enzyme in sphingolipid metabolism. Recent studies have shown that myeloid cells contribute to the elevated expression of AC, such that the conditional loss in these cell types protects from acute colitis. We crossed conditional ASAH1 LyzMCRE knockout mice with IL10 knockout mice to determine the role of AC in a model of spontaneous, chronic colitis. Colon tissues were analyzed for lipids, mRNA, and protein. We performed flow cytometry to determine the role of myeloid AC in recruiting immune cells in disease. In this study, the conditional loss of AC in myeloid cells protected from chronic colitis, reduced markers of inflammation, increased ceramides in the colon, and reduced the inflammatory metabolite sphingosine-1-phosphate (S1P). Recruitment of immune cells into intestinal tissue was significantly impaired, specifically recruitment of neutrophils and effector Th1/Th17 T cells. The findings from this study indicate that AC may be a promising therapeutic target for patients with inflammatory bowel disease by modulating sphingolipid metabolism in immune cells.