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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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722003470 |
| _version_ | 1797954097990598656 |
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| author | Kaushik Sen Rashmirekha Pati Atimukta Jha Gyan Prakash Mishra Subhasish Prusty Shweta Chaudhary Swati Swetalika Sreeparna Podder Aishwarya Sen Mamuni Swain Ranjan Kumar Nanda Sunil K. Raghav |
| author_facet | Kaushik Sen Rashmirekha Pati Atimukta Jha Gyan Prakash Mishra Subhasish Prusty Shweta Chaudhary Swati Swetalika Sreeparna Podder Aishwarya Sen Mamuni Swain Ranjan Kumar Nanda Sunil K. Raghav |
| author_sort | Kaushik Sen |
| collection | DOAJ |
| 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 NCoR1DC−/−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. |
| first_indexed | 2024-04-10T23:13:19Z |
| format | Article |
| id | doaj.art-5d05db2ab1fd4342a94eef70d154ac16 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:13:19Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-5d05db2ab1fd4342a94eef70d154ac162023-01-13T04:16:17ZengElsevierRedox Biology2213-23172023-02-0159102575NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidationKaushik Sen0Rashmirekha Pati1Atimukta Jha2Gyan Prakash Mishra3Subhasish Prusty4Shweta Chaudhary5Swati Swetalika6Sreeparna Podder7Aishwarya Sen8Mamuni Swain9Ranjan Kumar Nanda10Sunil K. Raghav11Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, IndiaTranslational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, IndiaTranslational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, IndiaInstitute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, India; Corresponding author. Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India.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 NCoR1DC−/−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.http://www.sciencedirect.com/science/article/pii/S2213231722003470NCoR1GlycolysisOXPHOSHIF-1αFAOTh1 |
| spellingShingle | Kaushik Sen Rashmirekha Pati Atimukta Jha Gyan Prakash Mishra Subhasish Prusty Shweta Chaudhary Swati Swetalika Sreeparna Podder Aishwarya Sen Mamuni Swain Ranjan Kumar Nanda Sunil K. Raghav NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation Redox Biology NCoR1 Glycolysis OXPHOS HIF-1α FAO Th1 |
| 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 | NCoR1 Glycolysis OXPHOS HIF-1α FAO Th1 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722003470 |
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