| Title: |
Acetyl-CoA carboxylase 1 inhibition increases Treg metabolism and graft-versus-host disease treatment efficacy via mitochondrial fusion |
| Authors: |
McDonald-Hyman, C; Aguilar, EG; Compeer, EB; Zaiken, MC; Rhee, SY; Mohamed, FA; Larson, JH; Loschi, ML; Lees, C; Thangavelu, G; Sleeth, ML; Smith, KD; Whangbo, JS; Ritz, J; Sparwasser, TD; O'Connor, RS; Crawford, PA; Rathmell, JC; Kean, LS; Zeiser, R; Hippen, KL; Dustin, ML; Blazar, BR |
| Publisher Information: |
American Society for Clinical Investigation |
| Publication Year: |
2025 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1172/jci182480 |
| DOI: |
10.1172/jci182480 |
| Availability: |
https://doi.org/10.1172/jci182480; https://ora.ox.ac.uk/objects/uuid:aee1d83e-7f7b-4615-9d07-40eec28e3652 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.E38307AC |
| Database: |
BASE |