Role for myeloid acid ceramidase in colon inflammation and cancer

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Bioactive lipids, such as ceramide and its downstream metabolites, sphingosine, and sphingosine-1-phosphate (S1P), mediate critical biologic responses, including inflammation and cancer1. Thus, the enzymes regulating lipid metabolism are intriguing therapeutic targets. The long-term goal of this project is to define the role of the bioactive sphingolipid metabolizing enzyme, acid ceramidase (AC), in colitis and colitis-associated cancer (CAC) and determine whether targeting this enzyme could serve as a novel anti-inflammatory/anti-CAC therapy. The PI’s laboratory has an established track record of expertise in sphingolipid metabolism and function2,3. Our recent work has begun to uncover a specific and very unique role for myeloid (Mye) AC in colitis and CAC. Using dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CAC in murine models, we found that AC expression is increased in the inflammatory infiltrate but not in the colon epithelium. Similarly, we observed increased AC expresion in tissue macrophages in humans with colitis and colon cancer. In conditional knockout mice deletion of AC in myeloid cells, (Mye AC cKO), but not intestinal epithelial cells, decreased immune infiltrate and protected mice from colitis and CAC. Moreover, we found that our AC-specific inhibitor, LCL521, attenuates inflammation in a chronic colitis model (IL10 deficient mice). Finally, our newest preliminary data using bone marrow derived macrophages (BMDMs) from Mye AC cKO mice strongly hint that Mye AC may be required for inflammatory responses in these cells. Together these data suggest that Mye AC plays a large role the development of colitis and CAC. Based on our substantial preliminary data, we hypothesize that loss of Mye AC activity is protective against colitis and CAC by modulating colonic inflammatory infiltrate, and that targeting Mye AC may result in novel disease-modifying therapy in colitis and CAC. This hypothesis will be tested by the following Specific Aims: Specific Aim 1. Establish that Mye AC cKO protects from chronic colitis and CAC in vivo. Specific Aim 2. Determine the mechanisms by which loss of Mye AC protects from chronic colitis in vivo and probe these mechanisms in cells. Specific Aim 3. Advance pharmacologic inhibition of AC as a novel colitis and CAC target. The significance of these studies lies in the unique role of AC as the ceramidase that is clearly important in colitis and CAC, and the potential for AC as a novel therapeutic target. Identifying the mechanisms by which AC regulates chronic colitis and CAC, with specific focus on Mye AC, is a crucial first step in the design of novel therapies targeting this pathway. In addition, the studies that target AC in specific mouse models of colitis and CAC, will allow us to begin to translate our studies into clinical therapeutic approaches in the very near future.