LncRNA IL21-AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus

Limin Liu; Longyuan Hu; Haojun Long; Meiling Zheng; Zhi Hu; Ye He; Xiaofei Gao; Pei Du; Hongjun Zhao; Di Yu; Qianjin Lu; Ming Zhao

doi:10.1002/ctm2.1117

LncRNA IL21-AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus

Clin Transl Med. 2022 Dec;12(12):e1117. doi: 10.1002/ctm2.1117.

Authors

Limin Liu^{1

2

3

4}, Longyuan Hu^{1

2

3}, Haojun Long^{1

2

3}, Meiling Zheng^{1

2

3}, Zhi Hu^{1

2

3}, Ye He^{1

2

3}, Xiaofei Gao^{1

2

3}, Pei Du^{1

2

3}, Hongjun Zhao⁵, Di Yu⁶, Qianjin Lu^{1

7}, Ming Zhao^{1

2

3}

Affiliations

¹ Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, China.
² Research Unit of Key Technologies of Diagnosis and Treatment for Immune-related Skin Diseases, Chinese Academy of Medical Sciences, Changsha, China.
³ Clinical Medical Research Center of Major Skin Diseases and Skin Health of Hunan Province, Changsha, China.
⁴ Department of Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.
⁵ Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, China.
⁶ The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
⁷ Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

Abstract

Background: The aberrant differentiation of T follicular helper (Tfh) cells plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of regulating Tfh cells differentiation remains unclear. Long noncoding RNAs (lncRNAs) act as important regulators in the processes of innate and adaptive immune response. Whether lncRNAs are involved in regulating Tfh cell differentiation and autoimmune responses need to be further identified.

Methods: The characters and functions of human IL21-AS1 and its mouse homologous lncRNA (mIl21-AS) were investigated by a series of biochemical assays and cell transfection assay. mIl21-AS1 regulating humoral immune response in vivo was explored by keyhole limpet haemocyanin (KLH) and chronic graft versus host disease (cGVHD) model.

Results: Human IL21-AS1 and its mouse homologous lncRNA (mIl21-AS) were identified and cloned. We uncovered that IL21-AS1 was highly expressed in CD4⁺ T cells of SLE patients and Tfh cells, which promoted differentiation of Tfh cells. Mechanistically, IL21-AS1 bound heterogeneous nuclear ribonucleoprotein U and recruited acetyltransferases CREB-binding protein to the promoter of IL21, leading to the transcriptional activation of IL21 and Tfh cells differentiation through increasing Histone H3 acetylation level on IL21 promoter. Moreover, Tfh proportion and antibodies production were significantly increased in mIl21-AS knock-in mice immunized with KLH. mIl21-AS1 overexpression also exacerbated the lupus-like phenotype in cGVHD mice model.

Conclusions: Our results demonstrate that IL21-AS1 activates IL21 transcription via epigenetic mechanism to promote germinal centre response, adding insight into the molecular regulation of autoimmune pathogenesis and providing a novel target for SLE treatment.

Keywords: autoimmunity; epigenetics; lncRNA; systemic lupus erythematosus.

Publication types

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

MeSH terms

Animals
Cell Differentiation / genetics
Cell Differentiation / immunology
Epigenesis, Genetic / genetics
Epigenesis, Genetic / immunology
Humans
Lupus Erythematosus, Systemic* / genetics
Lupus Erythematosus, Systemic* / immunology
Mice
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / immunology
T Follicular Helper Cells* / immunology

Substances

interleukin-21
RNA, Long Noncoding