Introduction
When the human body is exposed to various factors, such as viral infection, aberrant secretion of immune factors, and genetic predispositions, a reduction in the immune system’s tolerance toward its own antigenic components occurs [1]. Consequently, this triggers a pathological autoimmune response characterized by the production of numerous autoantibodies and immune complexes, resulting in tissue damage and organ dysfunction. This condition is referred to as an autoimmune disease. On the basis of the extent of organ and tissue involvement, these diseases can be classified into either organ-specific or systemic autoimmune diseases, such as autoimmune hepatitis and primary biliary cholangitis, or systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and scleroderma. In 1999, autoimmune diseases were classified by the World Health Organization as the third leading cause of mortality, following cardiovascular diseases and cancers. Moreover, they were also included in China’s medium- and long-term science and technology programs as one of the top ten major diseases. Globally, the overall incidence rate of autoimmune diseases is approximately 0.09% [2], and the prevalence ranges from 7.6% to 9.4% [3]. The incidence and prevalence of this disease vary significantly depending on the specific type of autoimmune disease. Nevertheless, there has been a general upward trend in their occurrence over recent decades.
Long noncoding RNAs (lncRNAs) are functional RNA molecules that lack protein translation ability. Initially, it was thought that lncRNAs do not have a biological function. However, with in-depth studies in the last decade, lncRNAs have been found to be functionally diverse and highly specific in controlling immune cell differentiation, and function. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), a widely known lncRNA, has been shown to be involved in viral infection [4], neurodegenerative diseases [5], autoimmune diseases [6], inflammatory diseases, cancers [7] and many other diseases. Hence, we address the current understanding of the relationship between NEAT1 and autoimmune diseases in this review.
Overview of <italic>NEAT1</italic>
NEAT1 serves as the central component of membraneless subcellular organelles known as paraspeckles. Paraspeckles are composed of the lncRNA NEAT1 and a variety of RNA-binding proteins located in the interchromosomal region of mammalian cells. NEAT1, as the main component, is essential for the formation of paraspeckles. It plays a supporting role in the nucleus and regulates gene expression [8]. These dynamic ribonucleoprotein complexes (RNPs) in paraspeckles play crucial roles in regulating transcription by sequestering specific proteins and RNA molecules, thereby influencing RNA processing. Additionally, NEAT1 functions as a molecular sponge for various microRNAs, impacting downstream RNA function [9, 10]. As discovered in 2007, the lncRNA NEAT1 is transcribed by Pol II from the MENI site on human chromosome 11q13 and is essential for the structural formation, and stability of paraspeckles [11]. Unlike many other lncRNAs that have limited expression and tissue specificity, NEAT1 is abundantly expressed and can be upregulated to promote paraspeckle formation during certain developmental stages, and during cellular stress [12].
There are two transcript isoforms of NEAT1, NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb), in humans, with the former being completely contained within the latter. NEAT1 contains three RNA domains, A, B, and C, which are involved in stabilization, isomer conversion, and paraspeckle assembly [13]. Both NEAT1_1 and NEAT1_2 are encoded by a single exon. While NEAT1_2 is confined to the nucleus, NEAT1_1 has been detected in both the cytoplasm and nucleus of acute myeloid leukemia (AML) cells [14]. NEAT1_1 is expressed in most human tissues, whereas NEAT1_2 expression is tissue-specific. Although the biological function of NEAT1 is attributed mainly to NEAT1_2, which is located in the nucleus and participates in the formation of paraspeckles, and the regulation of gene expression, NEAT1_1 exists predominantly in the cytoplasm of cells, affecting posttranscriptional regulation [15]. NEAT1 is regulated by a variety of transcription factors, such as p53, HIF1α, ERα, Oct4, and ATF2, under different conditions [8, 16–18]. The two transcripts share the same 5’ end. Moreover, NEAT1_1 possesses a classical polyadenosine signal (PAS) at its 3’ end, whereas NEAT1_2 lacks a typical poly(A) tail but features a characteristic triple helix structure at its 3’ end. Notably, the middle domain element of NEAT1_2 can recruit 54 kD nuclear RNA- and DNA-binding protein (p54nrb), which is also known as non-POU-domain-containing octamer-binding protein (NONO), to initiate the formation of paraspeckles [8]. These transcripts exhibit significant differences in biogenesis and processing, subnuclear localization, and gene expression.
Research progress on the role of <italic>NEAT1</italic> in autoimmune diseases
<italic>NEAT1</italic> and SLE
SLE is a chronic autoimmune disease characterized by multisystem damage that can affect the skin, serous membranes, joints, kidneys, central nervous system, etc. The pathological manifestation involves the deposition of autoantibodies and immune complexes [19], the exact cause of which remains incompletely understood. Studies have revealed significantly elevated expression of NEAT1 in the peripheral blood mononuclear cells (PBMCs) of patients with SLE compared with healthy individuals. NEAT1 is upregulated in monocytes, one of the major components of the innate immune system, and its expression is stimulated by lipopolysaccharide (LPS) via the p38-mediated pathway, which promotes the activation of mitogen-activated protein kinases (MAPK) and increases the expression of the cytokines IL-6 and CXCL10. Additionally, the downregulation of NEAT1 inhibits the expression of chemokines and cytokines such as IL-6 and CXCL10, resulting in a positive correlation between them [20]. As a competitive endogenous RNA, NEAT1 can serve as a sponge to bind with miR-365a-3p, effectively promoting the expression and secretion of IL-6 in monocyte-derived dendritic cells (moDCs) [21]. In addition, the expression of NEAT1 in the PBMCs of SLE patients is significantly increased, which disrupts the balance of Th1 and Th2 cells, increases the proportion of Th2 cells, promotes the secretion of IL-4, and ultimately enhances the body’s immune response [22]. However, excessive production of chemokines and cytokines may play a role in SLE pathogenesis.
Furthermore, Dong et al. [23] reported a correlation between the pathogenesis of SLE and the activation of interferon (IFN)-I signaling in B cells. Moreover, NEAT1 was overexpressed in granulocyte-myeloid-derived suppressor cells (G-MDSCs) from MRL/lpr mice. G-MDSCs with elevated NEAT1 expression were found to secrete B-cell activating factor (BAFF), subsequently inhibiting the expression of suppressor of cytokine signaling-3 (SOCS-3). This dysregulation ultimately leads to abnormal activation of the IFN-I signaling pathway in B cells and consequently contributes to the development of SLE. More directly, in their pristane-induced lupus mouse model, the lack of NEAT1 alleviated lupus symptoms, reducing urinal protein levels, spleen size, the serum level of anti-dsDNA antibody, kidney infiltration by immune cells, and IgG and IgM deposition in the glomerulus.
<italic>NEAT1</italic> and RA
RA is another chronic systemic autoimmune disease primarily characterized by progressive joint erosion and destruction, with the main pathological changes being synovial inflammation, cartilage matrix damage, and marginal bone invasion [24]. Studies indicate that the lncRNA NEAT1 is significantly upregulated not only in the PBMCs of patients with RA [25] but also in the synovial tissues of patients with RA and in fibroblast-like synoviocytes (FLSs) [26]. miR-23a, a member of the miR-23a-27a-24-2 cluster, is capable of regulating cellular motility, cellular activation, and immune cell infiltration [27]. Moreover, the lncRNA NEAT1 can inhibit the expression of miR-23a [28]. Murine double minute-2 (MDM2) is the downstream target gene of miR-23a, and its ubiquitination can decrease the expression of sirtuin 6 (SIRT6) during the onset of RA [29]. Previously, Kawahara et al. [30] reported that SIRT6 can inhibit the activation of the nuclear factor κB (NF-κB) signaling pathway by reducing the acetylation level of histone 3 lysine 9 (H3K9) in downstream target genes of NF-κB. Similarly, SIRT6 plays a crucial role in the regulation of FLS, which is a pivotal regulator of RA and a major contributor to synovial hyperplasia [31].
In addition, the differentiation of CD4+ T cells into Th17 cells is an important factor affecting the occurrence and development of RA. Liu et al. [32] reported that the lncRNA NEAT1 was significantly downregulated in activated CD4+ T lymphocytes but was moderately upregulated during the differentiation of CD4+ T cells to Th17 cells in vitro. In contrast, Shui et al. [33] reported that the knockdown of NEAT1 reduced the protein level of STAT3, a key transcription factor for Th17 cell differentiation, which in turn inhibited the differentiation of CD4+ T cells into Th17 cells and blocked the development of RA.
<italic>NEAT1</italic> and psoriasis
Psoriasis is an immune-mediated, chronic inflammatory skin disease characterized by recurrent squamous erythema or plaques that can be localized or widespread. The etiology of psoriasis is multifactorial and involves both environmental and genetic factors. Furthermore, keratinocytes exhibit abnormal hyperproliferation and differentiation in response to nonspecific stimuli such as microbial infection, chemical stimulation, and trauma, leading to the development of this disease [34].
Recent studies have demonstrated significant upregulation of the lncRNA NEAT1 in 3 mm deep psoriatic lesion tissue samples, which is positively correlated with the expression levels of inflammatory factors, including IL-6, IL-8, TNF-α, IL-17, and IL-22 [35]. Conversely, the lncRNA NEAT1 is expressed at low levels in the skin tissues of patients with psoriasis. Wang et al. [36] reported that upregulation of NEAT1 resulted in the targeted mediation of downstream miR-3194-5p to increase Galectin-7 expression, which subsequently inhibited the activity of psoriasis HaCat cells and exhibited therapeutic effects. In a mouse model of psoriasis, high expression of NEAT1 and STAT3 was observed in skin lesion tissue from the model group, whereas miR-485-5p was expressed at low levels due to complementary binding sites with NEAT1 [37]. Notably, STAT3 plays crucial roles in various pathophysiological processes associated with psoriasis, including Th17 cell differentiation, epidermal cell hyperproliferation, and abnormal differentiation, abnormal dermal vascular hyperplasia, and inflammatory cell infiltration [38].
<italic>NEAT1</italic> and multiple sclerosis
Chronic autoimmune disease of the central nervous system, known as multiple sclerosis (MS), is mediated primarily by CD4+ T cells and characterized by spatial and temporal multiplicity. It predominantly affects young and middle-aged individuals, with a higher prevalence among women. The primary clinical manifestations are inflammatory demyelination and neuronal degeneration [39].
Dysregulation of Th17 and Treg populations is pivotal in the pathogenesis of MS. Furthermore, FOXP3 exerts a regulatory effect on Treg cell stability, and its reduced expression hampers Treg cell differentiation, thereby disrupting immune cell balance and homeostasis. A study demonstrated significant upregulation of NEAT1 expression in PBMCs from MS patients, concomitant with decreased FOXP3 expression. RNA sequencing (RNA-seq) analysis also revealed greater NEAT1 expression in effector Th17 cells than in primary Th17 cells [40]. Th1/Th2 imbalances are commonly observed in individuals with autoimmune diseases such as psoriasis and RA. In the context of MS, both Th1-related TNF-α and Th17-related IL-17 are positively correlated with NEAT1 levels, greatly increasing susceptibility to MS [41].