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LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708910/ https://www.ncbi.nlm.nih.gov/pubmed/36447054 http://dx.doi.org/10.1002/ctm2.1117 |
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author | Liu, Limin Hu, Longyuan Long, Haojun Zheng, Meiling Hu, Zhi He, Ye Gao, Xiaofei Du, Pei Zhao, Hongjun Yu, Di Lu, Qianjin Zhao, Ming |
author_facet | Liu, Limin Hu, Longyuan Long, Haojun Zheng, Meiling Hu, Zhi He, Ye Gao, Xiaofei Du, Pei Zhao, Hongjun Yu, Di Lu, Qianjin Zhao, Ming |
author_sort | Liu, Limin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9708910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97089102022-12-02 LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus Liu, Limin Hu, Longyuan Long, Haojun Zheng, Meiling Hu, Zhi He, Ye Gao, Xiaofei Du, Pei Zhao, Hongjun Yu, Di Lu, Qianjin Zhao, Ming Clin Transl Med Research Articles 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. John Wiley and Sons Inc. 2022-11-29 /pmc/articles/PMC9708910/ /pubmed/36447054 http://dx.doi.org/10.1002/ctm2.1117 Text en © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Liu, Limin Hu, Longyuan Long, Haojun Zheng, Meiling Hu, Zhi He, Ye Gao, Xiaofei Du, Pei Zhao, Hongjun Yu, Di Lu, Qianjin Zhao, Ming LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title | LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title_full | LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title_fullStr | LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title_full_unstemmed | LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title_short | LncRNA IL21‐AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus |
title_sort | lncrna il21‐as1 interacts with hnrnpu protein to promote il21 overexpression and aberrant differentiation of tfh cells in systemic lupus erythematosus |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708910/ https://www.ncbi.nlm.nih.gov/pubmed/36447054 http://dx.doi.org/10.1002/ctm2.1117 |
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