Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration

Rocca, Claudia La; Carbone, Fortunata; Rosa, Veronica De; Colamatteo, Alessandra; Galgani, Mario; Perna, Francesco; Lanzillo, Roberta; Morra, Vincenzo Brescia; Orefice, G; Cerillo, Ilaria; Florio, Ciro; Maniscalco, Giorgia Teresa; Salvetti, Marco; Centonze, Diego; Uccelli, Antonio; Longobardi, Salvatore; Visconti, Andrea; Matarese, Giuseppe

doi:10.1016/j.metabol.2017.08.011

Cited by 74 publications

(59 citation statements)

References 37 publications

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“…The increased glucose metabolism after inhibition of miR‐31‐5p in human CD4 + T cells is in accordance with reports of increased glycolysis in immune cells from SLE patients and mouse models of lupus . Furthermore, IFNβ treatment of RRMS patients has been reported to restore the reduced levels of glycolysis in patient T cells . In all, our results indicate that miR‐31‐5p is regulator of T‐cell energy metabolism during type I IFN responses.…”

Section: Discussionsupporting

confidence: 91%

miR‐31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome

et al. 2018

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Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNβ and in patients with Sjögren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4 + T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN-α also increased the basal levels of human CD4 + T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.Keywords: Autoimmunity r Interferons r Immune regulation r Metabolism r Rheumatology Additional supporting information may be found online in the Supporting Information section at the end of the article.by the overexpression of a large set of IFN-stimulated genes (ISGs) collectively termed the IFN signature [1,2]. Type I IFNs signal through the heterodimeric IFNA receptor and induce the expression of ISGs, several of which have important antiviral * These authors contributed equally.

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Section: Discussionsupporting

confidence: 91%

miR‐31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome

et al. 2018

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“…Several researchers have studied the effects of IFN-β treatment either on peripheral nTreg or iTreg [9][10][11][12][13][14][15], but no previous study has investigated the modulation of nTreg and their subsets, Tr1 and Tr1-like cells in the same cohort of patients. Most reports on Treg are based on cross-sectional studies and limited by selection bias, such as a small number of included patients and a short follow-up.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantification of natural and inducible regulatory T-cell subsets during interferon-β therapy of multiple sclerosis patients

Chiarini¹,

Capra

Serana³

et al. 2020

J Transl Med

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Background: The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility. Methods: In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-β-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells. Results: Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-β treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-β therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pretreatment Tr1-like cells.

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“…The deletion of autoreactive lymphocytes is normally mediated by apoptosis, however, an escape from mitochondria-mediated apoptosis has been reported in lymphocytes of MS patients [12]. Mitochondria from MS lymphocytes also show a decrease of mitochondrial respiration [13] associated with a specific decrease of complex I and complex IV activities [28], and, of note, mitochondria have been found to range in shape and size and showed thickened cristae [29]. Mitochondrial dependent apoptosis is also depending on mitochondrial respiration, shape and structure.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that deletion of autoreactive lymphocytes by apoptosis is defective in patients with MS, thereby permitting these cells to perpetuate a continuous cycle of inflammation within the CNS [10,11]. In particular, the impairment of mitochondria-mediated apoptosis in Cd4+ T lymphocytes [12], as well as, a reduction of mitochondrial respiration are reported in MS patients [13]. Mitochondria have a main role in both cell death and life and they are a major source of reactive oxygen species (ROS) production.…”

Section: Introductionmentioning

confidence: 99%

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

et al. 2020

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Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins. Among others, optic atrophy 1 (OPA1) protein plays a key role in the regulating mitochondrial dynamics, cristae architecture and release of pro-apoptotic factors. Very interesting, mutations in OPA1 gene, have been associated with multiple sclerosis-like disorder. We have analyzed OPA1 and some factors involved in its regulation. Fifteen patients with MS and fifteen healthy control subjects (HC) were enrolled into the study and peripheral blood mononuclear cells (PBMCs) were isolated. H2O2 level was measured spectrofluorimetrically, OPA1, PHB2, SIRT3, and OMA1 were analyzed by western blotting. Statistical analysis was performed using Student’s t-test. The results showed that PBMC of MS patients were characterized by a deregulation of OPA1 processing associated with increased H2O2 production, inactivation of OMA1 and increase of PHB2 protein level. The presented data suggest that the alteration of PHB2, OMA1, and OPA1 processing could be involved in resistance towards apoptosis. These molecular parameters could also be useful to assess disease activity.

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Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration

Cited by 74 publications

References 37 publications

miR‐31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome

miR‐31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome

Simultaneous quantification of natural and inducible regulatory T-cell subsets during interferon-β therapy of multiple sclerosis patients

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

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