The Long Noncoding RNA MALAT1 Induces Tolerogenic Dendritic Cells and Regulatory T Cells via miR155/Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Nonintegrin/IL10 Axis

Jian Wu; Hanlu Zhang; Yang Zheng; Xiangyuan Jin; Mingyang Liu; Shuang Li; Qi Zhao; Xianglan Liu; Yongshun Wang; Ming Shi; Shengnan Zhang; Jinwei Tian; Yong Sun; Maomao Zhang; Bo Yu

doi:10.3389/fimmu.2018.01847

The Long Noncoding RNA MALAT1 Induces Tolerogenic Dendritic Cells and Regulatory T Cells via miR155/Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Nonintegrin/IL10 Axis

Front Immunol. 2018 Aug 13:9:1847. doi: 10.3389/fimmu.2018.01847. eCollection 2018.

Authors

Jian Wu^{1

2}, Hanlu Zhang^{1

2}, Yang Zheng^{1

2}, Xiangyuan Jin³, Mingyang Liu^{1

2}, Shuang Li^{1

2}, Qi Zhao^{1

2}, Xianglan Liu^{1

2}, Yongshun Wang⁴, Ming Shi⁵, Shengnan Zhang^{1

2}, Jinwei Tian^{1

2}, Yong Sun^{1

2}, Maomao Zhang^{1

2}, Bo Yu^{1

2}

Affiliations

¹ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
² The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
³ Department of Thoracic Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, China.
⁴ School of Biomedical Sciences, The University of Hong Kong, Pokfulam, China.
⁵ School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

Abstract

By shaping T cell immunity, tolerogenic dendritic cells (tDCs) play critical roles in the induction of immune tolerance after transplantation. However, the role of long noncoding RNAs (lncRNAs) in the function and immune tolerance of dendritic cells (DCs) is largely unknown. Here, we found that the lncRNA MALAT1 is upregulated in the infiltrating cells of tolerized mice with cardiac allografts and activated DCs. Functionally, MALAT1 overexpression favored a switch in DCs toward a tolerant phenotype. Mechanistically, ectopic MALAT1 promoted dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) expression by functioning as an miR155 sponge, which is essential for the tolerogenic maintenance of DCs and the DC-SIGN-positive subset with more potent tolerogenic ability. The adoptive transfer of MALAT1-overexpressing DCs promoted cardiac allograft survival and protected from the development of experimental autoimmune myocarditis, accompanied with increasing antigen-specific regulatory T cells. Therefore, overexpressed MALAT1 induces tDCs and immune tolerance in heart transplantation and autoimmune disease by the miRNA-155/DC-SIGH/IL10 axis. This study highlights that the lncRNA MALAT1 is a novel tolerance regulator in immunity that has important implications in settings in which tDCs are preferred.

Keywords: IL10; MALAT1 long noncoding RNA; dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin; immune tolerance; miR155; tolerogenic dendritic cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
Autoimmune Diseases / genetics
Autoimmune Diseases / immunology*
Cell Adhesion Molecules / metabolism
Cell Differentiation
Cells, Cultured
Dendritic Cells / immunology*
Heart Transplantation*
Immune Tolerance
Interleukin-10 / metabolism
Lectins, C-Type / metabolism
Lymphocyte Activation
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
MicroRNAs / genetics*
Models, Animal
Myocarditis / genetics
Myocarditis / immunology*
Organ Specificity
RNA, Long Noncoding / genetics*
Receptors, Cell Surface / metabolism
Signal Transduction
T-Lymphocytes, Regulatory / immunology*

Substances

Cell Adhesion Molecules
DC-specific ICAM-3 grabbing nonintegrin
Lectins, C-Type
MALAT1 long non-coding RNA, human
MicroRNAs
Mirn155 microRNA, mouse
RNA, Long Noncoding
Receptors, Cell Surface
Interleukin-10