Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring DOI Creative Commons
Valentina Pucino, Michelangelo Certo, Vinay Bulusu

и другие.

Cell Metabolism, Год журнала: 2019, Номер 30(6), С. 1055 - 1074.e8

Опубликована: Ноя. 7, 2019

Accumulation of lactate in the tissue microenvironment is a feature both inflammatory disease and cancer. Here, we assess response immune cells to context chronic inflammation. We report that accumulation inflamed contributes upregulation transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated uptake into induces reshaping their effector phenotype, resulting increased IL17 production via nuclear PKM2/STAT3 enhanced fatty acid synthesis. It also leads cell retention as consequence reduced glycolysis Furthermore, antibody-mediated blockade ameliorates severity murine model arthritis. Finally, propose lactate/SLC5A12-induced metabolic reprogramming distinctive lymphoid synovitis rheumatoid arthritis patients potential therapeutic target disorders.

Язык: Английский

Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer DOI Creative Commons
Maik Luu, Zeno Riester,

Adrian Baldrich

и другие.

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 1, 2021

Abstract Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show short-chain fatty acids (SCFAs) pentanoate and butyrate enhance anti-tumor cytotoxic T lymphocytes (CTLs) chimeric antigen receptor (CAR) through metabolic epigenetic reprograming. We in vitro treatment CTLs CAR with increases function mTOR as a central cellular sensor, inhibits class I histone deacetylase activity. This reprogramming results elevated production effector molecules such CD25, IFN-γ TNF-α, significantly enhances antigen-specific ROR1-targeting syngeneic murine melanoma pancreatic cancer models. Our shed light onto may used for enhancing immunity. Collectively, identify two SCFAs therapeutic utility context immunotherapy.

Язык: Английский

Процитировано

425
Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions DOI Creative Commons
Ashley V. Menk, Nicole E. Scharping,

Rebecca S. Moreci

и другие.

Cell Reports, Год журнала: 2018, Номер 22(6), С. 1509 - 1521

Опубликована: Фев. 1, 2018

To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative in which glucose is fermented into lactate rather than oxidized mitochondria. However, the signaling events that initiate glycolysis remain unclear. We show cell activation rapidly induces independent transcription, translation, CD28, and Akt not involving increased uptake or activity glycolytic enzymes. Rather, TCR promotes pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import facilitating breakdown lactate. Inhibition PDHK1 reveals this switch required acutely for cytokine synthesis but dispensable cytotoxicity. Functionally, modulated via dehydrogenase, represses mRNA translation when disengaged. Our data provide mechanistic insight metabolic contribution effector function suggest may be finely tuned through modulation activity.

Язык: Английский

Процитировано

406
Glycolysis – a key player in the inflammatory response DOI Creative Commons
Gonzalo Soto‐Heredero, Manuel M. Gómez de las Heras, Enrique Gabandé‐Rodríguez

и другие.

FEBS Journal, Год журнала: 2020, Номер 287(16), С. 3350 - 3369

Опубликована: Апрель 7, 2020

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora agents, and maintain tissue homoeostasis. On one hand, cells involved in pro‐inflammatory response, such as M1 macrophages, Th1 Th17 lymphocytes or activated microglia, must rapidly provide energy fuel inflammation, which is essentially accomplished glycolysis high lactate production. other regulatory T M2 are immune regulation resolution preferentially use fatty acid oxidation through TCA cycle main source for Here, we discuss impact glycolytic metabolism at different steps response. Finally, review wide variety molecular mechanisms could explain relationship between metabolites phenotype, including signalling events, epigenetic remodelling, post‐transcriptional post‐translational modifications. Inflammatory processes common feature many age‐associated diseases, cardiovascular neurodegenerative disorders. finding that immunometabolism be master regulator inflammation broadens avenue treating inflammation‐related pathologies manipulation vascular metabolism.

Язык: Английский

Процитировано

404
Helper T cell differentiation DOI Open Access
Jordy Saravia, Nicole M. Chapman, Hongbo Chi

и другие.

Cellular and Molecular Immunology, Год журнала: 2019, Номер 16(7), С. 634 - 643

Опубликована: Март 12, 2019

Процитировано

399
Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring DOI Creative Commons
Valentina Pucino, Michelangelo Certo, Vinay Bulusu

и другие.

Cell Metabolism, Год журнала: 2019, Номер 30(6), С. 1055 - 1074.e8

Опубликована: Ноя. 7, 2019

Accumulation of lactate in the tissue microenvironment is a feature both inflammatory disease and cancer. Here, we assess response immune cells to context chronic inflammation. We report that accumulation inflamed contributes upregulation transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated uptake into induces reshaping their effector phenotype, resulting increased IL17 production via nuclear PKM2/STAT3 enhanced fatty acid synthesis. It also leads cell retention as consequence reduced glycolysis Furthermore, antibody-mediated blockade ameliorates severity murine model arthritis. Finally, propose lactate/SLC5A12-induced metabolic reprogramming distinctive lymphoid synovitis rheumatoid arthritis patients potential therapeutic target disorders.

Язык: Английский

Процитировано

385