SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation
Abstract Inflammatory diseases implicate a synchronised immune-metabolic rewiring to maintain homeostasis. The regulatory mechanisms governing the transcriptional control of immune-centric metabolic adjustments in dendritic cells (DCs) remains elusive. Recently we reported that Ncor2 (SMRT) loss of...
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Nature Portfolio
2024-12-01
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| Series: | npj Metabolic Health and Disease |
| Online Access: | https://doi.org/10.1038/s44324-024-00034-1 |
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| author | Kaushik Sen Rashmirekha Pati Gyan Prakash Mishra Subhasish Prusty Sourya Prakash Nayak Archana Tripathy Shweta Chaudhary Atimukta Jha Arunita Patra Priti Meena Shaktiprasad Mishra Ranjan Kumar Nanda Alok Kumar Mantri Bhawna Gupta Sunil K. Raghav |
| author_facet | Kaushik Sen Rashmirekha Pati Gyan Prakash Mishra Subhasish Prusty Sourya Prakash Nayak Archana Tripathy Shweta Chaudhary Atimukta Jha Arunita Patra Priti Meena Shaktiprasad Mishra Ranjan Kumar Nanda Alok Kumar Mantri Bhawna Gupta Sunil K. Raghav |
| author_sort | Kaushik Sen |
| collection | DOAJ |
| description | Abstract Inflammatory diseases implicate a synchronised immune-metabolic rewiring to maintain homeostasis. The regulatory mechanisms governing the transcriptional control of immune-centric metabolic adjustments in dendritic cells (DCs) remains elusive. Recently we reported that Ncor2 (SMRT) loss of function in DCs potentiates strong inflammation. We found that SMRT depletion in DCs triggers a metabolic shift resulting in sustained and strong inflammation despite reduced glycolysis. This is in contrast to the widely accepted notion that glycolytic pathway activation is essential for inducing inflammation. Downregulation of mTOR emerged as a pivotal factor in attenuating the glycolytic rate. Significant metabolic alterations led to rewiring of the TCA-cycle by triggering anaplerotic glutamine catabolism and promoting succinate oxidation, thereby sustaining the inflammatory potential. Simultaneous treatment with succinate transport inhibitor DEBM and mTOR inducer Mhy1485 remarkably suppressed inflammation ex vivo and in vivo. Our findings also depicted an inverse correlation between SMRT levels with human autoimmune diseases. |
| format | Article |
| id | doaj-art-2cb071a283f34025aa92dc5600e877d5 |
| institution | OA Journals |
| issn | 2948-2828 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Metabolic Health and Disease |
| spelling | doaj-art-2cb071a283f34025aa92dc5600e877d52025-08-20T02:31:17ZengNature Portfolionpj Metabolic Health and Disease2948-28282024-12-012111610.1038/s44324-024-00034-1SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidationKaushik Sen0Rashmirekha Pati1Gyan Prakash Mishra2Subhasish Prusty3Sourya Prakash Nayak4Archana Tripathy5Shweta Chaudhary6Atimukta Jha7Arunita Patra8Priti Meena9Shaktiprasad Mishra10Ranjan Kumar Nanda11Alok Kumar Mantri12Bhawna Gupta13Sunil K. Raghav14Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Translational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Department of Nephrology, All India Institute of Medical SciencesImmunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Translational Health Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)Department of Gastroenterology, Utkal HospitalKalinga Institute of Industrial TechnologyImmunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS)Abstract Inflammatory diseases implicate a synchronised immune-metabolic rewiring to maintain homeostasis. The regulatory mechanisms governing the transcriptional control of immune-centric metabolic adjustments in dendritic cells (DCs) remains elusive. Recently we reported that Ncor2 (SMRT) loss of function in DCs potentiates strong inflammation. We found that SMRT depletion in DCs triggers a metabolic shift resulting in sustained and strong inflammation despite reduced glycolysis. This is in contrast to the widely accepted notion that glycolytic pathway activation is essential for inducing inflammation. Downregulation of mTOR emerged as a pivotal factor in attenuating the glycolytic rate. Significant metabolic alterations led to rewiring of the TCA-cycle by triggering anaplerotic glutamine catabolism and promoting succinate oxidation, thereby sustaining the inflammatory potential. Simultaneous treatment with succinate transport inhibitor DEBM and mTOR inducer Mhy1485 remarkably suppressed inflammation ex vivo and in vivo. Our findings also depicted an inverse correlation between SMRT levels with human autoimmune diseases.https://doi.org/10.1038/s44324-024-00034-1 |
| spellingShingle | Kaushik Sen Rashmirekha Pati Gyan Prakash Mishra Subhasish Prusty Sourya Prakash Nayak Archana Tripathy Shweta Chaudhary Atimukta Jha Arunita Patra Priti Meena Shaktiprasad Mishra Ranjan Kumar Nanda Alok Kumar Mantri Bhawna Gupta Sunil K. Raghav SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation npj Metabolic Health and Disease |
| title | SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation |
| title_full | SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation |
| title_fullStr | SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation |
| title_full_unstemmed | SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation |
| title_short | SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation |
| title_sort | smrt depleted conventional dcs maintain inflammation despite lower glycolysis via mtor signalling and succinate oxidation |
| url | https://doi.org/10.1038/s44324-024-00034-1 |
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