Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Angiari, S; Carlucci, T; Budui, SL; Bach, SD; Dusi, S; Walter, J; Ellmeier, E; Schnabl, A; Stracke, A; Bordag, N; Tafrali, C; Demjaha, R; Khalil, M; Angelini, G; Terrabuio, E; Pietronigro, EC; Zenaro, E; Laudanna, C; Rossi, B; Constantin, G.
Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.
J Neuroinflammation. 2024; 21(1): 287 Doi: 10.1186/s12974-024-03270-w [OPEN ACCESS]
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Leading authors Med Uni Graz

Angiari Stefano

Co-authors Med Uni Graz

Bordag Natalie

Demjaha Rina

Ellmeier Elena

Khalil Michael

Meissel Julia

Schnabl Alyssa

Stracke Anika

Tafrali Cansu

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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.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Encephalomyelitis, Autoimmune, Experimental - immunology, metabolism, pathology

Mice - administration & dosage

Humans - administration & dosage

Coenzyme A - metabolism

Pantetheine - analogs & derivatives, pharmacology, metabolism

Mice, Inbred C57BL - administration & dosage

T-Lymphocytes - metabolism, immunology, drug effects

Female - administration & dosage

Neuroinflammatory Diseases - metabolism, immunology

Mice, Transgenic - administration & dosage

Find related publications in this database (Keywords)

CoA metabolism

Pantethine

Autoreactive T cells

EAE

Multiple sclerosis

Immunometabolism

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