ABSTRACT

 

Nuclear Receptor Co-repressor NCoR1 governs immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation

 

Kaushik Sen, Rashmirekha Pati, Atimukta Jha, Gyan Prakash Mishra, Subhasish Prusty, Shweta Chaudhary, Swati Swetalika, Sreeparna Podder, Aishwarya Sen, Mamuni Swain, Ranjan Nanda, Sunil K. Raghav

 

Author Affiliations

India Institute of Life Sciences, Bhubaneshwar, Odisha-751023

 

Correspondence: Dr. Kaushik Sen

sen.k3736@gmail.com

 

IJIR. 2023;(7)1:A1

 

Published: 31 January 2023

© IJIR

Abstract

Dendritic cells (DCs) undergo rapid metabolic reprogramming events to induce signal-specific immune responses. The transcriptional control of energy metabolism in tolerogenic-DCs remains elusive. We have recently reported that NCoR1 ablation in DCs leads to immune tolerance by altering the balance of naive T helper cells towards T-regs. Here, comprehensive metabolic profiling of these tolerogenic DCs identified that they meet their anabolic requirements through enhanced glycolysis and OxPhos, supported by FAO-driven oxygen consumption. Mechanistically, AKT, mTOR, and HIF-1α-axis mediated glycolysis and CPT1a-driven β-oxidation were found to be enhanced in the NCoR1-depleted DCs. In addition, reduced pyruvate and glutamine oxidation, with a broken TCA cycle, and PPAR-γ-induced β-oxidation maintain the tolerogenic state of the cells. Additionally, we showed how the tolerogenic cytokines IL-10 and IL-27 and the overall transcriptional signature of immunological tolerance were considerably compromised by the combined suppression of HIF-1α and CPT1a using KC7F2 and Etomoxir respectively. Interestingly, this combined treatment further cleared the Mycobacterium tuberculosis (Mtb) burden in BMcDC1s ex-vivo and in CD103⁺ lung DCs in NCoR1DC ^-/- mice in-vivo. Furthermore, the spleen of these infected mice also showed treatment-induced increased Th1-mediated IFN-γ responses. Ultimately, to validate the findings in the human system, we demonstrated that dexamethasone-derived primary human tolerogenic moDCs showed significantly reduced NCoR1 expression, which in turn suppressed the CD4 T-cell proliferation and Th1 phenotype at the expense of T-regs. Here, the combined treatment rescued the T-cell proliferative capacity and the Th1 phenotype. Our findings demonstrate that increased glycolysis and fatty acid oxidation fine-tune immune tolerance versus inflammation in murine and human DCs.

 

Presented by: Kaushik Sen