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NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation

Dendritic cells (DCs) undergo rapid metabolic reprogramming to generate signal-specific immune responses. The fine control of cellular metabolism underlying DC immune tolerance remains elusive. We have recently reported that NCoR1 ablation generates immune-tolerant DCs through enhanced IL-10, IL-27...

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Autores principales: Sen, Kaushik, Pati, Rashmirekha, Jha, Atimukta, Mishra, Gyan Prakash, Prusty, Subhasish, Chaudhary, Shweta, Swetalika, Swati, Podder, Sreeparna, Sen, Aishwarya, Swain, Mamuni, Nanda, Ranjan Kumar, Raghav, Sunil K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804250/
https://www.ncbi.nlm.nih.gov/pubmed/36565644
http://dx.doi.org/10.1016/j.redox.2022.102575
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author Sen, Kaushik
Pati, Rashmirekha
Jha, Atimukta
Mishra, Gyan Prakash
Prusty, Subhasish
Chaudhary, Shweta
Swetalika, Swati
Podder, Sreeparna
Sen, Aishwarya
Swain, Mamuni
Nanda, Ranjan Kumar
Raghav, Sunil K.
author_facet Sen, Kaushik
Pati, Rashmirekha
Jha, Atimukta
Mishra, Gyan Prakash
Prusty, Subhasish
Chaudhary, Shweta
Swetalika, Swati
Podder, Sreeparna
Sen, Aishwarya
Swain, Mamuni
Nanda, Ranjan Kumar
Raghav, Sunil K.
author_sort Sen, Kaushik
collection PubMed
description Dendritic cells (DCs) undergo rapid metabolic reprogramming to generate signal-specific immune responses. The fine control of cellular metabolism underlying DC immune tolerance remains elusive. We have recently reported that NCoR1 ablation generates immune-tolerant DCs through enhanced IL-10, IL-27 and SOCS3 expression. In this study, we did comprehensive metabolic profiling of these tolerogenic DCs and identified that they meet their energy requirements through enhanced glycolysis and oxidative phosphorylation (OXPHOS), supported by fatty acid oxidation-driven oxygen consumption. In addition, the reduced pyruvate and glutamine oxidation with a broken TCA cycle maintains the tolerogenic state of the cells. Mechanistically, the AKT-mTOR–HIF–1α-axis mediated glycolysis and CPT1a-driven β-oxidation were enhanced in these tolerogenic DCs. To confirm these observations, we used synthetic metabolic inhibitors and found that the combined inhibition of HIF-1α and CPT1a using KC7F2 and etomoxir, respectively, compromised the overall transcriptional signature of immunological tolerance including the regulatory cytokines IL-10 and IL-27. Functionally, treatment of tolerogenic DCs with dual KC7F2 and etomoxir treatment perturbed the polarization of co-cultured naïve CD4(+) T helper (Th) cells towards Th1 than Tregs, ex vivo and in vivo. Physiologically, the Mycobacterium tuberculosis (Mtb) infection model depicted significantly reduced bacterial burden in BMcDC1 ex vivo and in CD103(+) lung DCs in Mtb infected NCoR1(DC−/−)mice. The spleen of these infected animals also showed increased Th1-mediated responses in the inhibitor-treated group. These findings suggested strong involvement of NCoR1 in immune tolerance. Our validation in primary human monocyte-derived DCs (moDCs) showed diminished NCOR1 expression in dexamethasone-derived tolerogenic moDCs along with suppression of CD4(+)T cell proliferation and Th1 polarization. Furthermore, the combined KC7F2 and etomoxir treatment rescued the decreased T cell proliferative capacity and the Th1 phenotype. Overall, for the first time, we demonstrated here that NCoR1 mediated control of glycolysis and fatty acid oxidation fine-tunes immune tolerance versus inflammation balance in murine and human DCs.
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spelling pubmed-98042502023-01-01 NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation Sen, Kaushik Pati, Rashmirekha Jha, Atimukta Mishra, Gyan Prakash Prusty, Subhasish Chaudhary, Shweta Swetalika, Swati Podder, Sreeparna Sen, Aishwarya Swain, Mamuni Nanda, Ranjan Kumar Raghav, Sunil K. Redox Biol Research Paper Dendritic cells (DCs) undergo rapid metabolic reprogramming to generate signal-specific immune responses. The fine control of cellular metabolism underlying DC immune tolerance remains elusive. We have recently reported that NCoR1 ablation generates immune-tolerant DCs through enhanced IL-10, IL-27 and SOCS3 expression. In this study, we did comprehensive metabolic profiling of these tolerogenic DCs and identified that they meet their energy requirements through enhanced glycolysis and oxidative phosphorylation (OXPHOS), supported by fatty acid oxidation-driven oxygen consumption. In addition, the reduced pyruvate and glutamine oxidation with a broken TCA cycle maintains the tolerogenic state of the cells. Mechanistically, the AKT-mTOR–HIF–1α-axis mediated glycolysis and CPT1a-driven β-oxidation were enhanced in these tolerogenic DCs. To confirm these observations, we used synthetic metabolic inhibitors and found that the combined inhibition of HIF-1α and CPT1a using KC7F2 and etomoxir, respectively, compromised the overall transcriptional signature of immunological tolerance including the regulatory cytokines IL-10 and IL-27. Functionally, treatment of tolerogenic DCs with dual KC7F2 and etomoxir treatment perturbed the polarization of co-cultured naïve CD4(+) T helper (Th) cells towards Th1 than Tregs, ex vivo and in vivo. Physiologically, the Mycobacterium tuberculosis (Mtb) infection model depicted significantly reduced bacterial burden in BMcDC1 ex vivo and in CD103(+) lung DCs in Mtb infected NCoR1(DC−/−)mice. The spleen of these infected animals also showed increased Th1-mediated responses in the inhibitor-treated group. These findings suggested strong involvement of NCoR1 in immune tolerance. Our validation in primary human monocyte-derived DCs (moDCs) showed diminished NCOR1 expression in dexamethasone-derived tolerogenic moDCs along with suppression of CD4(+)T cell proliferation and Th1 polarization. Furthermore, the combined KC7F2 and etomoxir treatment rescued the decreased T cell proliferative capacity and the Th1 phenotype. Overall, for the first time, we demonstrated here that NCoR1 mediated control of glycolysis and fatty acid oxidation fine-tunes immune tolerance versus inflammation balance in murine and human DCs. Elsevier 2022-12-16 /pmc/articles/PMC9804250/ /pubmed/36565644 http://dx.doi.org/10.1016/j.redox.2022.102575 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Sen, Kaushik
Pati, Rashmirekha
Jha, Atimukta
Mishra, Gyan Prakash
Prusty, Subhasish
Chaudhary, Shweta
Swetalika, Swati
Podder, Sreeparna
Sen, Aishwarya
Swain, Mamuni
Nanda, Ranjan Kumar
Raghav, Sunil K.
NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title_full NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title_fullStr NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title_full_unstemmed NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title_short NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
title_sort ncor1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804250/
https://www.ncbi.nlm.nih.gov/pubmed/36565644
http://dx.doi.org/10.1016/j.redox.2022.102575
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