Ulcerative colitis (UC) is a chronic and debilitating inflammatory disease that affects the inner lining of the colon and rectum. UC is one of the major forms of inflammatory bowel disease and represents a significant risk factor for the development of colorectal cancer. The pathophysiology of UC remains incompletely understood; this is in part due to the complex interplay of factors that regulate the mechanism of disease. The current data indicates that UC develops in genetically susceptible individuals that exhibit a dysfunctional mucosal immune response triggered by environmental factors. Thus, there is a need for increased understanding of the genetic and environmental components that regulate the activation of the immune system and inflammation, the molecular mechanism of tissue damage and the process involved in healing. Understanding how these processes are regulated will lead to the development of efficient therapies to treat UC. Sphingolipids are a class of novel bioactive lipids that regulate membrane structure and multiple cellular processes. Recently, our group established sphingosine kinase 1 (SK1) and its metabolic product sphingosine- 1-phosphate (S1P) as critical regulators of systemic and local inflammation in the mouse model of DSS- induced colitis. To elucidate the molecular mechanism of SK1 function in colon inflammation it is critical to identify the metabolic pathway of S1P generation. Ceramidases break down ceramide to generate sphingosine, the substrate metabolite of SK1. Because ceramidases are critical regulators of S1P generation upstream of SK1, we aimed to identify the specific ceramidase implicated in regulating the colonic inflammatory response. Our preliminary data identified acid ceramidase (AC), as the potential ceramidase involved in regulating the inflammatory response implicated in the pathology of UC. Furthermore, our work has begun to uncover novel and specific roles for AC in regulating the inflammatory response of innate immune cells. Based on this new and exiting direction, this proposal aims to investigate the hypothesis that myeloid- derived AC contributes to UC by regulating production of inflammatory cytokines in innate immune cells such as macrophages. To investigate this hypothesis, we proposed to demonstrate that AC myeloid conditional knock out (cKO) mice are protected from DSS-induced colitis manifestations and probe the mechanisms involved. In addition, we aim to define the specific role and mechanism of AC in macrophage cell function. Addressing these aims will not only further our understanding of the role of sphingolipids in inflammation and UC, but will also investigate novel roles of AC in regulating cell biology.
Ulcerative colitis (UC) is a chronic inflammatory condition that affects the inner lining of the colon and rectum. UC is one of the major forms of inflammatory bowel disease and represents a significant risk factor for the development of colorectal cancer. Although complete understanding of the etiology of IBD is lacking, the current model points to a complex interplay between environmental factors that trigger chronic intestinal inflammation in a genetically susceptible host. Thus, there is a need for increased understanding of the genetic and environmental components that regulate the activation of the immune system and inflammation, the molecular mechanism of tissue damage and the process involved in healing. Clearly, understanding how these processes are regulated will lead to the development of efficient therapies to treat UC. Bioactive sphingolipids are established regulators of inflammation and play a critical role in the inflammatory response characteristic in UC. In this proposal, we aim to further our understanding of the molecular mechanisms of sphingolipid-mediated inflammation and to elucidate the specific and novel role of the sphingolipid metabolic enzyme acid ceramidase in regulating innate immunity. This work will provide insight into fundamental mechanisms of inflammation that can serve as potential targets for novel therapeutics in UC.
|Espaillat, Mel Pilar; Snider, Ashley J; Qiu, Zhijuan et al. (2018) Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. FASEB J 32:2339-2353|
|Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2017) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul 63:140-155|