SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation
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.
Authors
- A. K. Tripathy (ORCID: https://orcid.org/0000-0001-6518-2114)
- Arunita Patra
- Ranjan Kumar Nanda (ORCID: https://orcid.org/0000-0002-2163-4411)
- GYAN PRAKASH MISHRA (ORCID: https://orcid.org/0000-0002-7023-2638)
- Subhasish Prusty
- Shaktiprasad Mishra (ORCID: https://orcid.org/0000-0001-7628-0510)
- Kaushik Sen (ORCID: https://orcid.org/0000-0002-4063-840X)
- Sunil K. Raghav (ORCID: https://orcid.org/0000-0001-9913-4241)
- Alok Kumar Mantri (ORCID: https://orcid.org/0000-0001-7163-8800)
- Priti Meena (ORCID: https://orcid.org/0000-0001-6073-8101)
- Bhawna Gupta (ORCID: https://orcid.org/0000-0001-8476-3942)
- Shweta Chaudhary (ORCID: https://orcid.org/0000-0002-0041-281X)
- Sourya Prakash Nayak
- Rashmirekha Pati
- Atimukta Jha
Institutions
- Regional Centre for Biotechnology (IN)
- All India Institute of Medical Sciences Bhubaneswar (IN)
- Institute of Life Sciences (IN)
- International Centre for Genetic Engineering and Biotechnology (IN)
- KIIT University (IN)
- Utkal University (IN)
Publication Details
- Journal
- npj Metabolic Health and Disease
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s44324-024-00034-1
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.24
Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Science and Engineering Research Board
- Biotechnology Industry Research Assistance Council