The ATP Citrate Lyase (ACLY) as regulator of gut T cell immunometabolism in inflammatory bowel diseases.

• Applicant: Privatdozentin Dr. Imke Atreya, Ph.D.
• Subject Area: Gastroenterology ; Clinical Immunology and Allergology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511510453

Inflammatory bowel diseases (IBD) affect nearly 8 million people worldwide and are characterized by chronically remitting episodes of severe gastrointestinal symptoms, which negatively impact on the quality of life and working ability of IBD patients and, overtime, can trigger the development of colorectal cancer. Thus, it is absolutely desirable to achieve a stable therapeutic control of the inflammatory process. However, despite the very successful introduction of new biological agents during the last three decades, which specifically interfere with the immunopathogenesis of IBD, still approximately 40% of IBD patients do not achieve a satisfactory and long-lasting response to the clinically established therapeutic regimens. In view of the resulting challenge to further optimize IBD therapy, it seems attractive to widen the current spectrum of immune cell-modulating factors of relevance in intestinal inflammation that can be addressed therapeutically. In this context, our project will focus on the process of immunometabolic T cell regulation in the inflamed mucosa of IBD patients, which still remains incompletely defined and potentially offers a broad spectrum of not yet fully considered therapeutic target structures. In particular, we are interested in the metabolic enzyme ATP Citrate Lyase (ACLY), which catalyzes the formation of acetyl-coenzyme A from mitochondria-released citrate and thereby impacts on important regulatory mechanisms in activated and expanding T cells. Our preliminary and unpublished analyses already indicated an inflammation-triggered downregulation of ACLY protein expression in the intestinal immune cell compartment in murine colitis and IBD patients and demonstrated a decreased colitis-inducing capacity of ACLY-deficient CD4+ T cells in vivo. Moreover, the short-chain fatty acid butyrate could be identified as a potent negative regulator of ACLY expression in CD4+ T cells. Based on the already acquired data, we aim on the experimental validation of the following hypothesis: By downregulating ACLY activity in lamina propria T cells, the mucosal immune system counteracts intestinal inflammation. Therapeutic enhancement of this process, for instance by increasing the availability of butyrate in the intestinal lamina propria or by targeting ACLY-initiated downstream signaling cascades in T cells, might thus promote resolution of inflammation in IBD. Moreover, following the presented work programme, we intend to identify the exact mechanisms through which the metabolic function of ACLY is translated into its immunomodulating capacity and, thereby, we hope to pave the way for innovative therapeutic strategies targeting T cell immunometabolism in IBD by interfering with ACLY function.

• DFG Programme: Research Grants