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

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.

Biological functions and clinic significance of SAF‑A (Review)

“…2B ). Similarly, IL21-anti-sense RNA 1 interacting with SAF-A binds to the IL21 promoter, which is essential for regulating IL21 transcription ( 33 ). Research on embryonic stem cells also revealed that not only does SAF-A bind to the Oct4 proximal promoter, but it also interacts with endogenous Pol II.…”

Undervalued and novel roles of heterogeneous nuclear ribonucleoproteins in autoimmune diseases: Resurgence as potential biomarkers and targets

“…With the engagement of hnRNP U, the noncoding transcript in T cells ( NTT )/ prostate and breast cancer overexpressed 1 ( PBOV1 ) axis enhanced the differentiation of monocytes and ensuing inflammatory responses, partly underlying the pathogenesis of RA (Yang et al, 2018). Likewise, IL21‐AS1 recruited CREB‐binding protein to and increased histone H3 acetylation at the IL‐21 promoter by binding to hnRNP U, therefore facilitating transcriptional activation of IL‐21 and differentiation of T follicular helper (Tfh) cells in SLE (L. Liu, Hu, et al, 2022). SNP rs11631591, an intronic variant within the SLE susceptibility locus near RAS guanyl‐releasing protein 1 ( RASGRP1 ) that regulates the ERK/mitogen‐activated protein kinase pathway, exhibited T‐cell‐specific enhancer activity and interacted with hnRNP K in a risk‐allele‐specific manner, while hnRNP K inhibition suppressed the expression of RASGRP1 and ERK phosphorylation in T cells (Molineros et al, 2019).…”

“…Liu, Yu, & Zhou, 2021; Wang et al, 2019). On the other hand, hnRNPs have been identified as autoantigens in a broad spectrum of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE; Caporali et al, 2005), and are newly proposed to be inflammation mediators in other ways (L. Liu, Hu, et al, 2022; Ma et al, 2022). Of particular note, immune responses to infectious microbes are also likely to trigger autoimmunity via the molecular mimicry, and hnRNPs could be the linchpin nodes (Levin et al, 2002).…”