The impact of acid ceramidase in myeloid cells on intestinal inflammation

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Arizona $100,228 on December 15, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct basic biomedical research investigating the role of acid ceramidase in myeloid cells on intestinal inflammation.

The research aims to elucidate how acid ceramidase—an enzyme highly expressed in inflammatory bowel disease and colitis-associated cancer—modulates myeloid cell function, immune cell recruitment, and progression of intestinal disease. The project examines sphingolipid metabolism in immune cells, building on preliminary data showing that loss of acid ceramidase in myeloid cells protected mice from acute and chronic colitis, reduced innate immune cell infiltration, altered adaptive immune cell populations, and increased colonic ceramide content. The study uses genetic models including dextran sulfate sodium-induced acute colitis and IL-10-deficient chronic colitis models to test the hypothesis that loss of acid ceramidase in myeloid cells impairs inflammatory signaling and immune cell recruitment.

Work is performed in Arizona. The period of performance runs from the award date through May 14, 2028. The University of Arizona, operating as the Arizona Board of Regents, is the recipient. This is a project grant, the standard assistance type for NIH investigator-initiated research.

Abstract

Sphingolipids play significant roles in mediating inflammation in disease. Patients with inflammatory bowel disease (IBD) and colitis associated cancer (CAC) demonstrate elevated expression of various sphingolipid metabolism enzymes. Acid ceramidase (AC) is highly expressed in disease and deacylates ceramide generating the product for the generation of the bioactive lipid sphingosine 1-phosphate (S1P). Samples from patients with IBD and colorectal cancer, and animal models of colitis, have identified tissue infiltrating macrophages to be a likely source of elevated AC expression; however, the role of AC and immune cell sphingolipid metabolism in IBD remains understudied. The goal of this proposal aims to elucidate the role of myeloid cell derived AC in the progression of IBD and determine the role of AC in immune cell recruitment in IBD. Several studies have implicated sphingolipid metabolism in IBD and CAC using genetic manipulation or pharmacologic inhibitors in mouse models. Many of these studies have examined total body knockouts; however, the contribution of immune cell specific sphingolipid metabolism has not been thoroughly investigated. Our lab has demonstrated that loss of AC in myeloid cells protected mice from acute colitis using dextran sulfate sodium (DSS). The preliminary data presented in this proposal have extended these studies assessing myeloid specific loss of AC in a model of chronic colitis utilizing IL-10 deficient mice. The loss of AC protected from colonic inflammation, increased ceramide content, and reduced innate immune cell infiltrate. Furthermore, loss of AC in myeloid cells altered adaptive immune cell populations in the colon and peripheral tissues, potentially indicating a role for AC in cell- to-cell communication. Our findings have led US to hypothesize that loss of AC in myeloid cells impairs inflammatory signaling, and immune cell recruitment or maturation to alleviate chronic colitis. We therefore propose the following specific aims: specific aim 1: determine the mechanism by which loss of AC protects from chronic colitis. Specific aim 2: determine the role of AC in t cell maturation and immune cell recruitment in colitis.