Journal of Neuroinflammation (Nov 2024)

Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation

  • Stefano Angiari,
  • Tommaso Carlucci,
  • Simona L. Budui,
  • Simone D. Bach,
  • Silvia Dusi,
  • Julia Walter,
  • Elena Ellmeier,
  • Alyssa Schnabl,
  • Anika Stracke,
  • Natalie Bordag,
  • Cansu Tafrali,
  • Rina Demjaha,
  • Michael Khalil,
  • Gabriele Angelini,
  • Eleonora Terrabuio,
  • Enrica C. Pietronigro,
  • Elena Zenaro,
  • Carlo Laudanna,
  • Barbara Rossi,
  • Gabriela Constantin

DOI
https://doi.org/10.1186/s12974-024-03270-w
Journal volume & issue
Vol. 21, no. 1
pp. 1 – 20

Abstract

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Abstract Background Immune cell metabolism governs the outcome of immune responses and contributes to the development of autoimmunity by controlling lymphocyte pathogenic potential. In this study, we evaluated the metabolic profile of myelin-specific murine encephalitogenic T cells, to identify novel therapeutic targets for autoimmune neuroinflammation. Methods We performed metabolomics analysis on actively-proliferating encephalitogenic T cells to study their overall metabolic profile in comparison to resting T cells. Metabolomics, phosphoproteomics, in vitro functional assays, and in vivo studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), were then implemented to evaluate the effect of metabolic targeting on autoreactive T cell pathogenicity. Finally, we confirmed the translational potential of our targeting approach in human pro-inflammatory T helper cell subsets and in T cells from MS patients. Results We found that autoreactive encephalitogenic T cells display an altered coenzyme A (CoA) synthesis pathway, compared to resting T cells. CoA fueling with the CoA precursor pantethine (PTTH) affected essential immune-related processes of myelin-specific T cells, such as cell proliferation, cytokine production, and cell adhesion, both in vitro and in vivo. Accordingly, pre-clinical treatment with PTTH before disease onset inhibited the development of EAE by limiting T cell pro-inflammatory potential in vivo. Importantly, PTTH also significantly ameliorated the disease course when administered after disease onset in a therapeutic setting. Finally, PTTH reduced pro-inflammatory cytokine production by human T helper 1 (Th1) and Th17 cells and by T cells from MS patients, confirming its translational potential. Conclusion Our data demonstrate that CoA fueling with PTTH in pro-inflammatory and autoreactive T cells may represent a novel therapeutic approach for the treatment of autoimmune neuroinflammation.

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