PMID- 36565644 OWN - NLM STAT- MEDLINE DCOM- 20230117 LR - 20230221 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 59 DP - 2023 Feb TI - NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation. PG - 102575 LID - S2213-2317(22)00347-0 [pii] LID - 10.1016/j.redox.2022.102575 [doi] LID - 102575 AB - 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-1alpha-axis mediated glycolysis and CPT1a-driven beta-oxidation were enhanced in these tolerogenic DCs. To confirm these observations, we used synthetic metabolic inhibitors and found that the combined inhibition of HIF-1alpha 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 naive 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Sen, Kaushik AU - Sen K AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, India. FAU - Pati, Rashmirekha AU - Pati R AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India. FAU - Jha, Atimukta AU - Jha A AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India. FAU - Mishra, Gyan Prakash AU - Mishra GP AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024, India. FAU - Prusty, Subhasish AU - Prusty S AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, India. FAU - Chaudhary, Shweta AU - Chaudhary S AD - Translational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India. FAU - Swetalika, Swati AU - Swetalika S AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India. FAU - Podder, Sreeparna AU - Podder S AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024, India. FAU - Sen, Aishwarya AU - Sen A AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, India. FAU - Swain, Mamuni AU - Swain M AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India. FAU - Nanda, Ranjan Kumar AU - Nanda RK AD - Translational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India. FAU - Raghav, Sunil K AU - Raghav SK AD - Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India; Regional Centre for Biotechnology, Faridabad, Haryana, 121001, India. Electronic address: sunilraghav@ils.res.in. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221216 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 130068-27-8 (Interleukin-10) RN - MSB3DD2XP6 (etomoxir) RN - 0 (Interleukin-27) RN - 0 (Fatty Acids) RN - 0 (NCOR1 protein, human) RN - 0 (Nuclear Receptor Co-Repressor 1) RN - 0 (Ncor1 protein, mouse) SB - IM MH - Humans MH - Mice MH - Animals MH - *Interleukin-10/metabolism MH - *Interleukin-27/metabolism MH - Dendritic Cells/metabolism MH - Immune Tolerance MH - Glycolysis MH - Fatty Acids/metabolism MH - Cell Differentiation MH - Cells, Cultured MH - Nuclear Receptor Co-Repressor 1/metabolism PMC - PMC9804250 OTO - NOTNLM OT - FAO OT - Glycolysis OT - HIF-1alpha OT - NCoR1 OT - OXPHOS OT - Th1 OT - Tregs COIS- Declaration of completing interest The authors declare no competing interests. EDAT- 2022/12/25 06:00 MHDA- 2023/01/18 06:00 PMCR- 2022/12/16 CRDT- 2022/12/24 18:22 PHST- 2022/10/23 00:00 [received] PHST- 2022/12/04 00:00 [revised] PHST- 2022/12/05 00:00 [accepted] PHST- 2022/12/25 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2022/12/24 18:22 [entrez] PHST- 2022/12/16 00:00 [pmc-release] AID - S2213-2317(22)00347-0 [pii] AID - 102575 [pii] AID - 10.1016/j.redox.2022.102575 [doi] PST - ppublish SO - Redox Biol. 2023 Feb;59:102575. doi: 10.1016/j.redox.2022.102575. Epub 2022 Dec 16.