Lactate: Fueling the fire starter

Certo, Michelangelo; Marone, Giancarlo; Paulis, Amato de; Mauro, Claudio; Pucino, Valentina

doi:10.1002/wsbm.1474

Cited by 31 publications

(29 citation statements)

References 112 publications

(192 reference statements)

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“…For example, targeting specific metabolic pathways has been demonstrated to reduce inflammation both in vitro and in vivo models of arthritis (Yan et al, 2015;Biniecka et al, 2016;Okano et al, 2017;Shen et al, 2017;Bustamante et al, 2018). In addition, targeting metabolic intermediates such as lactate (Pucino et al, 2018;Certo et al, 2019) or succinate (Littlewood-Evans et al, 2016), is also becoming an attractive possibility. Animal models remain a crucial tool for preclinical screening of new therapeutics in pharmaceutical development.…”

Section: Conclusion and Further Perspectivesmentioning

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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Section: Conclusion and Further Perspectivesmentioning

confidence: 99%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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“…Lactate uptake by CD4 + T cells has been implicated in inhibiting migratory capability, essentially arresting T cells in the lactate hi microenvironment ( Figure 1 ). Also, lactate availability fostered differentiation of a Th17 subset, further supporting the chronic inflammatory process ( 49 , 54 ). As reported by Pucino et al, synovial T cells adapt to their milieu by upregulating the lactate transporter SLC5A12.…”

Section: Glucose Metabolism As An Arthritogenic Risk Factormentioning

confidence: 77%

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

Qiu

Goodman

et al. 2021

Front. Immunol.

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Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

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“…Moreover, comprising evidence underlines the importance of lactate as a signaling molecule especially in the inflammatory processes. Presence of lactate regulates immune cell polarization, differentiation and growth, as well as tumor immune surveillance [ 12 ]. These findings suggest that lactate could potentially be developed as metabolic biomarker for inflammatory disease and tumor stratification, as well as therapy response monitoring.…”

Section: Discussionmentioning

confidence: 99%

Hyperpolarized 13C Spectroscopy with Simple Slice-and-Frequency-Selective Excitation

et al. 2021

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Hyperpolarized 13C nuclear magnetic resonance spectroscopy can characterize in vivo tissue metabolism, including preclinical models of cancer and inflammatory disease. Broad bandwidth radiofrequency excitation is often paired with free induction decay readout for spectral separation, but quantification of low-signal downstream metabolites using this method can be impeded by spectral peak overlap or when frequency separation of the detected peaks exceeds the excitation bandwidth. In this work, alternating frequency narrow bandwidth (250 Hz) slice-selective excitation was used for 13C spectroscopy at 7 T in a subcutaneous xenograft rat model of human pancreatic cancer (PSN1) to improve quantification while measuring the dynamics of injected hyperpolarized [1-13C]lactate and its metabolite [1-13C]pyruvate. This method does not require sophisticated pulse sequences or specialized radiofrequency and gradient pulses, but rather uses nominally spatially offset slices to produce alternating frequency excitation with simpler slice-selective radiofrequency pulses. Additionally, point-resolved spectroscopy was used to calibrate the 13C frequency from the thermal proton signal in the target region. This excitation scheme isolates the small [1-13C]pyruvate peak from the similar-magnitude tail of the much larger injected [1-13C]lactate peak, facilitates quantification of the [1-13C]pyruvate signal, simplifies data processing, and could be employed for other substrates and preclinical models.

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Lactate: Fueling the fire starter

Cited by 31 publications

References 112 publications

Metabolic Checkpoints in Rheumatoid Arthritis

Metabolic Checkpoints in Rheumatoid Arthritis

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

Hyperpolarized 13C Spectroscopy with Simple Slice-and-Frequency-Selective Excitation

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