miR-142 controls metabolic reprogramming that regulates dendritic cell activation
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Published April 8, 2019
Citation Information: J Clin Invest. 2019;129(5):2029-2042. https://doi.org/10.1172/JCI123839.
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Research Article Hematology Immunology

miR-142 controls metabolic reprogramming that regulates dendritic cell activation

Abstract

DCs undergo metabolic reprogramming from a predominantly oxidative phosphorylation (OXPHOS) to glycolysis to mount an immunogenic response. The mechanism underpinning the metabolic reprogramming remains elusive. We demonstrate that miRNA-142 (miR-142) is pivotal for this shift in metabolism, which regulates the tolerogenic and immunogenic responses of DCs. In the absence of miR-142, DCs fail to switch from OXPHOS and show reduced production of proinflammatory cytokines and the ability to activate T cells in vitro and in in vivo models of sepsis and alloimmunity. Mechanistic studies demonstrate that miR-142 regulates fatty acid (FA) oxidation, which causes the failure to switch to glycolysis. Loss- and gain-of-function experiments identified carnitine palmitoyltransferase -1a (CPT1a), a key regulator of the FA pathway, as a direct target of miR-142 that is pivotal for the metabolic switch. Thus, our findings show that miR-142 is central to the metabolic reprogramming that specifically favors glycolysis and immunogenic response by DCs.

Authors

Yaping Sun, Katherine Oravecz-Wilson, Sydney Bridges, Richard McEachin, Julia Wu, Stephanie H. Kim, Austin Taylor, Cynthia Zajac, Hideaki Fujiwara, Daniel Christopher Peltier, Thomas Saunders, Pavan Reddy

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Figure 4

Effect of miR-142 deficiency on glycolysis after LPS stimulation of DCs.

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Effect of miR-142 deficiency on glycolysis after LPS stimulation of DCs....
(A) Enrichment score of gene set for glycolysis pathway in WT and miR-142–/– DCs (biological triplicates) by GSEA. (B and C) WT and miR-142–/– DCs were treated with diluent control or LPS and assessed for lactate production without 2-DG (B) and with 2-DG (C). Data (mean ± SEM) are combined from 3 similar experiments. Expression of GLUT1 in miR-142–/– and WT DCs after LPS treatment was determined for mRNA expression by qPCR (D) and for protein expression by FACS (E) (mean ± SEM). Data from 3 similar experiments were combined. (F) Glucose uptake (2-DG6P) and (G) HK2 mRNA expression in WT and miR-142–/– DCs treated with LPS. Data (mean ± SEM) are from 1 of 3 experiments. (H) AMPK activation in WT and miR-142–/– DCs untreated or treated with LPS for indicated times was examined by Western blot. (I) After treatment with LPS, activation of AKT and PRAS (30 minutes) or STAT3 (6 hours) in WT and miR-142–/– DCs was examined by Western blot. Comparisons between 2 groups were calculated using paired Student’s t test (2 tailed), while comparisons between 2 groups at multiple time points were calculated utilizing multiple t tests (Holm-Šidák method). *P < 0.05.