NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation

Lipid metabolism in dendritic cell biology

“…The above studies suggest that FAO likely promotes the DC tolerogenic phenotype. Consistent with this notion, inhibiting FAO attenuates the tolerogenic phenotype in primary human moDCs and an immortalized cDC1‐like cell line 67,68 . Accordingly, inhibition of FAO by targeting Cpt1a using shRNAs in GM‐CSF BMDCs rectifies the defects in activating CD8 + T‐cell proliferation, with such defects being attributed to elevated WNT5A‐induced β‐catenin activity and PPARγ‐dependent FAO 51 ; the β‐catenin–PPARγ axis is also reported to induce cDC1 and cDC2 tolerization in visceral adipose tissue 69 .…”

“…Consistent with this notion, inhibiting FAO attenuates the tolerogenic phenotype in primary human moDCs and an immortalized cDC1-like cell line. 67,68 Accordingly, inhibition of FAO by targeting Cpt1a using shRNAs in GM-CSF BMDCs rectifies the defects in activating CD8 + T-cell proliferation, with such defects being attributed to elevated WNT5A-induced β-catenin activity and PPARγ-dependent FAO 51 ; the β-catenin-PPARγ axis is also reported to induce cDC1 and cDC2 tolerization in visceral adipose tissue. 69 In addition, abrogation of FAO by etomoxir or inhibition of FAO by PPARα inhibitor GW6471 in GM-CSF BMDCs also leads to an increased capacity in priming CD8 + T cells (Figure 1D).…”

Mitochondria in innate immunity signaling and its therapeutic implications in autoimmune diseases

“…This is because DCs are non-proliferative cells ( 144 ). Additionally, glucose uptake increases at the early stages of DC activation, but as time progresses, OXPHOS becomes the dominant energy source required ( 145 ).…”

“…Inhibition of FAO by etomoxir significantly reduces the secretory levels of tolerogenic cytokines IL-10 and IL-27 whereas proinflammatory cytokines IL-12 and IL-6 remain stable. Moreover, compromised tolerogenic DCs under treatment with dual KC7F2, a selective HIF-1α translation inhibitor, and etomoxir perturb the polarization of naïve CD4+ Th cells towards Th1 ( 145 ). Additionally, in DCs, upregulation of PPARα induced by tumor-derived exosomes promotes FAO activity and shifts the predominant pattern from glycolysis toward OXPHOS, resulting in a dysfunctional state.…”

“…However, the HIF-1α expression in the tolerogenic DCs is more stabilized and coordinated by increased AKT and mTORC1, responsible for the upregulation of several glycolytic enzymes to promote this metabolism. KC7F2, a HIF-1α inhibitor, significantly reduces the percentage of HIF-1α positive tolerogenic DCs and suppresses the secretion of tolerogenic cytokines, without affecting the production of proinflammatory cytokines ( 145 ).…”