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.
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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

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Figure 6

MIR4435-2HG is expressed in subsets of mDCs with phenotypic features of increased activation and function.

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MIR4435-2HG is expressed in subsets of mDCs with phenotypic features of...
(A) tSNE map displaying the concatenated mDCs from ECs (n = 8) and HIVNs (n = 13) in 7 clusters identified by FlowSOM. (B) Heatmap showing the MFI of the parameters measured in the 7 mDC clusters from A. (C) Global tSNE map of concatenated mDCs, with mDCs from ECs and HIVNs overlaid (top). tSNE map showing the expression of individual phenotypic markers measured by flow cytometry (bottom). (D) Pie charts displaying the average frequencies of the 7 clusters in each cohort. Mann Whitney U test was used to compare the frequencies of each cluster between ECs and HIVNs, whereas χ2 test was used to compare the overall frequency distribution. (E) The MFIs of MIR4435-2HG were compared among 7 clusters in ECs and HIVNs. Mann Whitney U test was used for comparison between ECs and HIVNs, whereas Friedman test was used to compare among clusters. (F) The multiplication product of cluster frequencies (D) and MIR4435-2HG MFI (E) was calculated as a composite read-out and compared as in E. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.