Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand, Cornelia M.; Zeisbrich, Markus; Goronzy, Jörg J.

doi:10.1016/j.coi.2017.04.010

Cited by 110 publications

(86 citation statements)

References 61 publications

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“…Based on the biochemistry of glucose catabolism, several predictions can be made, if CD4 T cells preferentially supply carbon to the PPP; including excess availability of NADPH, reductive pressure, lack of metabolites for mitochondria, and preference for reductive biosynthetic reactions, such as fatty acid synthesis. All of these predictions hold for patient‐derived CD4 T cells: they favor lipogenesis and disfavor mitochondrial activity, and they have low ROS concentrations, imposing reductive instead of oxidative stress.…”

Section: Ra Cd4 T Cells Shunt Glucose Toward the Pentose Phosphate Pamentioning

confidence: 97%

“…Work from the last 10 years has identified a series of molecules mechanistically involved in redirecting differentiating CD4 T cells away from transitioning into protective memory T cells and instead forcing such T cells to become cytokine-producing, tissue-invasive, hypermigratory effector T cells that that are highly efficient in driving synovial membrane inflammation. [7][8][9][10] These molecules are presented in Figure 1. The common denominator of how these molecules affect CD4 T cell function lies in the regulation of the cell cycle and the programming of metabolic cascades.…”

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confidence: 99%

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Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

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In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.

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Section: Ra Cd4 T Cells Shunt Glucose Toward the Pentose Phosphate Pamentioning

confidence: 97%

mentioning

confidence: 99%

Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

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“…). Both pathways are mechanistically connected to cellular metabolism, opening the intriguing possibility of modulating immune function through metabolic interference …”

Section: Metabolic Control Of Pd‐l1 Expressionmentioning

confidence: 99%

The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease

Weyand

Berry

Goronzy

2017

Journal of Leukocyte Biology

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Because of their vital function, the wall structures of medium and large arteries are immunoprivileged and protected from inflammatory attack. That vascular immunoprivilege is broken in atherosclerosis and in vasculitis, when wall-invading T cells and macrophages (Mϕ) promote tissue injury and maladaptive repair. Historically, tissue-residing T cells were studied for their antigen specificity, but recent progress has refocused attention to antigen-nonspecific regulation, which determines tissue access, persistence, and functional differentiation of T cells. The coinhibitory receptor PD-1, expressed on T cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, Mϕ, and endothelial cells to attenuate T cell activation, effector functions, and survival. Through mitigating signals, the PD-1 immune checkpoint maintains tissue tolerance. In line with this concept, dendritic cells and Mϕs from patients with the vasculitic syndrome giant cell arteritis (GCA) are PD-L1 ; including vessel-wall-embedded DCs that guard the vascular immunoprivilege. GCA infiltrates in the arterial walls are filled with PD-1 T cells that secrete IFN-γ, IL-17, and IL-21; drive inflammation-associated angiogenesis; and facilitate intimal hyperplasia. Conversely, chronic tissue inflammation in the atherosclerotic plaque is associated with an overreactive PD-1 checkpoint. Plaque-residing Mϕs are PD-L1 , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1 Mϕs render patients with coronary artery disease immunocompromised and suppress antiviral immunity, including protective anti-varicella zoster virus T cells. Thus, immunoinhibitory signals affect several domains of vascular inflammation; failing PD-L1 in vasculitis enables unopposed immunostimulation and opens the flood gates for polyfunctional inflammatory T cells, and excess PD-L1 in the atherosclerotic plaque disables tissue-protective T cell immunity.

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“…Both peripheral and tissue resident RA CD4 + T cells have a unique metabolic signature (Weyand et al, 2017;Pucino et al, 2019). Indeed, RA CD4 + T cells exhibit an impairment in engaging glycolysis.…”

Section: Glucose Metabolismmentioning

confidence: 99%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.

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Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Cited by 110 publications

References 61 publications

Immunometabolism in the development of rheumatoid arthritis

Immunometabolism in the development of rheumatoid arthritis

The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease

Metabolic Checkpoints in Rheumatoid Arthritis

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