ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo

Author:

Schulz-Kuhnt Anja,Rühle Katharina,Javidmehr Asal,Döbrönti Michael,Biwank Jana,Knittel Selina,Neidlinger Peter,Leupold Jannik,Liu Li-Juan,Dedden Mark,Taudte Regina Verena,Gessner Arne,Fromm Martin F,Mielenz Dirk,Kreiss Lucas,Waldner Maximilian J,Schürmann Sebastian,Friedrich Oliver,Dietel Barbara,López-Posadas RocíoORCID,Plattner Christina, ,Zundler SebastianORCID,Becker ChristophORCID,Atreya RajaORCID,Neurath Markus FORCID,Atreya ImkeORCID

Abstract

ObjectiveMucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD.DesignACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models.ResultsACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+and to a lesser extent in CD8+T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhighCD4+T cells and ameliorated chronic colitis.ConclusionACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

Funder

Deutsche Forschungsgemeinschaft

Publisher

BMJ

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