Implications of immunometabolism for smouldering MS pathology and therapy

Bittner, Stefan; Pape, Katrin; Klotz, Luisa; Zipp, Frauke

doi:10.1038/s41582-023-00839-6

Cited by 3 publications

(1 citation statement)

References 154 publications

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“…Indeed, Trm were localized preferentially within inflammatory regions containing activated microglia/macrophages, and depletion of Trm correlated with a decrease in microglial activation. Therefore, Trm might be fueling a lowgrade chronic inflammation activating local myeloid cells, and likely also astrocytes, which in turn promote further demyelination and neuroaxonal damage, prevent remyelination or both (40)(41)(42)(43)(44). Similarly, in a murine model of CD8 + T cell mediated encephalitis, CD8 + T cells were important to attract phagocytes that caused synaptic loss (45).…”

Section: Discussionmentioning

confidence: 99%

CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Pignata,

Frieser,

Hsiao

et al. 2024

Preprint

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Therapeutic options against multiple sclerosis (MS) preventing T cell migration to the central nervous system (CNS) have remarkable clinical effects against the relapsing-remitting (RRMS) form of the disease, while they are poorly effective against its progressive form (PMS). Disability progression in PMS is thought to result from an interplay between smoldering local inflammation and neurodegeneration. We postulated that an ongoing inflammatory process mediated by CNS-resident memory CD4+ T cells (CD4+ Trm) could contribute to promote disease chronicity independently of de novo recruitment of peripheral autoreactive T cells. Indeed, our results revealed the presence of bona fide CD4+ Trm expressing CD69, CXCR6, P2RX7, CD49a and the transcription factor Hobit in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in the brain of persons with PMS. Single-cell transcriptional analysis uncovered their transcriptional heterogeneity and inflammatory potential and, accordingly, CD4+ Trm preferentially localized within inflammatory lesions. Finally, depletion of both the recirculating and the CNS-resident CD4+ T cell compartments was required to alleviate neurological signs during the chronic phase of EAE. Our results, therefore, indicate that CD4+ Trm actively contribute to maintain a chronic inflammatory state in the CNS, promoting damage and/or preventing repair, and suggest that new therapeutic strategies for the treatment of PMS should consider targeting the CNS-resident T cell compartment.

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Section: Discussionmentioning

confidence: 99%

CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Pignata,

Frieser,

Hsiao

et al. 2024

Preprint

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Bimodal accurate H₂O₂ regulation to equalize tumor-associated macrophage repolarization and immunogenic tumor cell death elicitation

Zhao,

Kong,

Zhu

et al. 2024

Chem. Sci.

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

Angiari,

Carlucci,

Budui

et al. 2024

J Neuroinflammation

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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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Implications of immunometabolism for smouldering MS pathology and therapy

Cited by 3 publications

References 154 publications

CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Bimodal accurate H₂O₂ regulation to equalize tumor-associated macrophage repolarization and immunogenic tumor cell death elicitation

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

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Implications of immunometabolism for smouldering MS pathology and therapy

Cited by 3 publications

References 154 publications

CD4+Trm sustain the chronic phase of auto-immune neuroinflammatory disease

CD4+Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Bimodal accurate H2O2 regulation to equalize tumor-associated macrophage repolarization and immunogenic tumor cell death elicitation

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

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CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

CD4⁺Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Bimodal accurate H₂O₂ regulation to equalize tumor-associated macrophage repolarization and immunogenic tumor cell death elicitation