Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers
Ciputra Adijaya Hartana, … , Mathias Lichterfeld, Xu G. Yu
Ciputra Adijaya Hartana, … , Mathias Lichterfeld, Xu G. Yu
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e146136. https://doi.org/10.1172/JCI146136.
View: Text | PDF
Research Article AIDS/HIV Immunology

Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers

Abstract

Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell–mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabolic state of mDCs, likely through epigenetic mechanisms involving H3K27ac enrichment at an intronic enhancer in the RPTOR gene locus, the main component of the mammalian target of rapamycin complex 1 (mTORC1). Together, these results suggest a role of MIR4435-2HG for enhancing immunometabolic activities of mDCs in ECs through targeted epigenetic modifications of a member of the mTOR signaling pathway.

Authors

Ciputra Adijaya Hartana, Yelizaveta Rassadkina, Ce Gao, Enrique Martin-Gayo, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu

×

Figure 8

MIR4435-2HG modulates functional metabolic activities in mDCs.

Options: View larger image (or click on image) Download as PowerPoint
MIR4435-2HG modulates functional metabolic activities in mDCs. (A) OCR ...
(A) OCR (left) and ECAR (right) of mDCs (n = 8) nucleofected with either MIR4435-2HG siRNA or scramble siRNA and stimulated with 2 μg/mL Poly(I:C) for 24 hours was measured at indicated time points in responses to oligomycin, FCCP, and rotenone/antimycin A using a Seahorse XFe96 Analyzer. (B) Basal respiration, maximal respiration, and spare respiratory capacity in mDCs from A were compared between MIR4435-2HG siRNA and scramble siRNA nucleofected cells. Wilcoxon matched pairs signed rank test was used as the statistical test. (C) Basal ECAR and OCR/ECAR ratio in mDCs from A were compared between MIR4435-2HG siRNA and scramble siRNA nucleofected cells. Wilcoxon matched pairs signed rank test was used as the statistical test. (D) Contour plots from a representative donor displaying the coexpression of MitoTracker (left) or ROS (right) to activation markers (CD40, CD83, and CD86) in mDCs nucleofected with either MIR4435-2HG siRNA or scramble siRNA and stimulated with 2 μg/mL Poly(I:C) for 24 hours. (E, F) The fold changes of frequencies of mDCs coexpressing MitoTracker or ROS and activation markers (CD40, CD83, and CD86) from D were compared. Wilcoxon matched pairs signed rank test was used as the statistical test. (G) A pseudocolor plot from a representative donor displaying allogeneic CD4+ and CD8+ T cell proliferations following the coculture with mDCs nucleofected with MIR4435-2HG siRNA or scramble siRNA and stimulated with 2 μg/mL Poly(I:C). (H) The frequencies of proliferating CD4+ and CD8+ T cells in mixed leukocyte reactions were compared (n = 7). Wilcoxon matched pairs signed rank test was used as the statistical test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.