H19 is an imprinted gene located on human chromosome 11p15.5 ( Figure 1 ) (25). Lnc RNA H19 is mainly expressed in the embryo, generally decreased at birth, and significantly increased in tumors (26). We found that H19 promotes epithelial-mesenchymal transformation, and its knockdown can inhibit the growth of multiple myeloma cells through the NF-κB pathway, suggesting that H19 may play a role in the development of inflammatory diseases (27). Zou et al. reported that overexpression of Lnc RNA H19 increased the abundance of miR-675p and decreased the expression of zonula occludin 1 (ZO-1) and E-cadherin (E-cad), thus destroying the integrity of the intestinal barrier (28). This process is blocked by ubiquitous RNA-binding protein HuR. In another study, miR-675p was identified as a regulator targeting the 3’-untranslated region (3’UTR) of VDR mRNA in ulcerative colitis patient tissues (29). H19 expression exhibited a negative correlation with vitamin D receptor (VDR) mRNA expression (29). In the above studies, we can speculate that Lnc RNA H19 increases the abundance of miR-675, which targets VDR mRNA, causes the decrease of ZO-1 and E-cad expression, and finally destroys the intestinal barrier. Based on the function of H19 as a competing endogenous RNA (ceRNA), another target of action for Lnc RNA H19 in the intestinal barrier was discovered (30, 31). Zhi et al. found that during acute intestinal ischemia, miR-874 promoted paracellular permeability by changing the level of TNF-α and TJ proteins through targeting the 3’UTR of aquaporin 3 (AQP3), causing disruption of intestinal barrier function (32). Su et al. verified that Lnc RNA H19, as a ceRNA, regulated the expression of AQP3 by competing with miR-874, causing intestinal barrier dysfunction (33).

Prostate cancer-upregulated long noncoding RNA1 (PLnc RNA1), a newly discovered lncRNA transcript, also known as CBR3 antisense RNA 1 (CBR3-AS1), located on chromosome 21q22.12, is upregulated in hepatocellular carcinoma (34), esophageal squamous cell carcinoma (35) and prostate cancer ( Figure 2 ) (36). Overexpressed PLnc RNA1 has been reported to protect the intestinal epithelial barrier from damage by dextran sulfate sodium (DSS) (37). This is due to the fact that miR-34c binds to PLnc RNA1 and can directly target the 3’UTR of Myc-associated zinc-finger protein (MAZ), thereby regulating the expression of ZO-1 and occludin to regulate intestinal barrier function. In addition, the knockdown of PLnc RNA1 can reduce the expression of MAZ, and its effect can be reversed by down-regulating miR-34c, which indicates that PLnc RNA1 can also directly regulate the expression of MAZ (37).

The SPROUTY4 intron transcript 1 (SPRY4-IT1) on chromosome 5q31.3 is transcribed from the SPRY4 gene ( Figure 3 ) (38). Previous studies have shown that SPRY4-IT1 is essential for maintaining basal epithelial barrier function. Xiao et al. found in a study that lncRNA SPRY4-IT1 protected intestinal barrier function by stabilizing TJ mRNA and enhancing its translation (39). This study showed that by silencing SPRY4-IT1, the mRNA expression of TJ proteins ocgludin, claudin-1, claudin-3 and JAM-1 could be reduced, resulting in impaired intestinal barrier function (39). Conversely, increasing the level of SPRY4-IT1 increased the expression of TJ protein, which promoted the function of the intestinal barrier (39). SPRY4-IT1 directly interacts with TJ mRNA, and SPRY4-IT1 can also bind to RNA-binding protein HuR and then interact with TJ mRNA to increase the number of TJ protein and promote the function of intestinal barrier.

Lnc RNA uc.173 is a transcribed ultra-conservative (T-UCR) region transcript representing the homologous region of human, rat, and mouse genomes ( Figure 4 ) (40). A study determined the expression of 21 T-UCR genes, including uc.173, in mouse intestinal mucosa from the whole genome profile analysis, and found that increasing the expression of Lnc RNA uc.173 gene could increase the growth of intestinal epithelial cells, while decreasing the expression level reduced the renewal of intestinal epithelial cells (IECs) (41). This is due to the fact that lncRNA uc.173 destroys the pri-miR-195 transcript and induces degradation of miR-195 to down-regulate the expression of miRNA195, thereby stimulating intestinal epithelial cell renewal. It was later found that the complementary sequence capable of interacting with Lnc RNA uc.173 was located in the central stem region of pri-miR-195 (upstream of the 3’ terminal), indicating that this region can control the degradation of pri-miRNA. However, the relationship between miR-195 and IECs has not been clearly clarified so far.

At present, the study of BC012900 is not thorough. A recent study reported that some cytokines such as TNF-α can regulate the expression of UC-related lncRNAs such as BC012900 (42). They further demonstrated that overexpression of BC012900 can significantly inhibit IEC cell proliferation and increase the sensitivity of IEC cells to apoptosis (42). However, the mechanism by which BC012900 further induces increased apoptosis in IEC cells is unclear. Since PPM1A expression is also increased in cells with increased BC012900 expression, they hypothesized that PPM1A expression may be one of the mechanisms by which BC012900 regulates apoptosis, based on previous reports that overexpression of PPM1A induces G2/M cell cycle arrest and apoptosis (43).

CRNDE is a gene symbol for Colorectal Neoplasia differentientially expression ( Figure 5 ) (44). It has been reported that Lnc CRNDE is highly expressed in colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, and decreased in renal pheochromocytoma and ovarian cancer (45). CRNDE may affect tumorigenesis through regulation of miRNAs (46, 47). Studies have found that CRNDE may be related to the progression of IBD (48). In colitis tissue and colonic epithelial cell lines induced by dextran sulfate sodium(DSS), CRNDE can inhibit miRNA-495 expression and increase the expression of cytokine signaling pathway inhibitor (SOCS1) (48). By interfering with the expression of CRNDE, IBD symptoms were alleviated in mice. Chu et al. found that miRNA-495 expression decreased in UC, and miRNA-495 could prevent IEC apoptosis through JAK signaling (49). It has also been suggested that SOCS1 can induce IEC apoptosis by promoting IFN-γ (50). Suppressor of cytokine signaling (SOCS1), a member of the cytokine signaling pathway inhibitor family, is induced by interferon (IFN)-γ-mediated JAK signaling pathway. It is widely considered to be a protein that restricts cytokine receptor signaling (51). In animal models of colitis, p53 has been proven to mediate apoptosis of IECs (52). Cui et al. showed that SOCS1 increased p53 phosphorylation and promoted IFN-γ-induced apoptosis of IECs (50). Therefore, it can be speculated that lnc CRNDE regulates IEC apoptosis through the CRNDE/miR-495/SOCS1 axis, which also indicates that CRNDE is a potential target for the treatment of IBD.

Lnc NEAT1 is a key component in building the ribo-riboprotein complex to regulate DNA-mediated activation of innate immune responses (53) and has also been found to play an important role in innate immune responses (54). Liu et al. found that NEAT1 was overexpressed in both DSS induced mouse models and tumor necrosis factor (TNF) -α-induced inflammatory cell models, and epithelial cell permeability increased in both mice and cell models compared to control cells (55). However, inhibition of NEAT1 can reverse its effects. This suggests that NEAT1 may affect the integrity and permeability of the intestinal epithelial barrier in patients with IBD. They also found that DSS could induce M1 macrophage activation, which was suppressed when NEAT1 expression was suppressed. Favre et al. demonstrated that low-dose photodynamic therapy (LDPDT) can improve T-cell-mediated colitis in mice (56). Subsequent studies have verified that PDT can alleviate DSS induced colitis in mice by regulating PI3K-AKT signaling pathway through Lnc NEAT1-miRNA204–5p axis, but whether PDT can alleviate clinical symptoms of IBD patients still needs further experimental verification (57).

CDKN2B-AS1 has more than 20 splicing variants, including typical splicing linear RNA and reverse splicing circular RNA molecules. Some studies have shown that downregulation of CDKN2B-AS1 can destroy Claudin-2 and cause the proliferation of intestinal epithelial cells, thus enhancing the intestinal barrier function (58). Another Lnc RNA, colon cancer-associated transcript 1 (CCAT1), was found to be overexpressed in IBD tissues. Ma et al. reported that CCAT1 expression was positively correlated with myosin light chain kinase (MLCK) (59). MLCK maintained the stability of MLCK mRNA by reducing the binding of miRNA-1853p to MLCK mRNA. MLCK and its phosphorylated products can increase intestinal permeability. CCAT1 and MLCK jointly accelerated the development of IBD (59).

The above studies suggest that lncRNAs not only regulate the apoptosis of epithelial cells in IBD, but also affect intestinal tight junction proteins and regulate the intestinal physical barrier through other mechanisms.

IFNG-AS1 is a non-coding transcript located on human chromosome 12 adjacent to the IFNG gene (66). By comparing adult UC patients, Jurkat T cell model and mouse colitis model, Padua et al. found that IFNG-AS1 was associated with IBD susceptibility locus SNP rs7134599, and IFNG-AS1 could positively regulate the key inflammatory factor IFNG in CD4 T cells (66). Gomez et al. demonstrated that IFNG-AS1 regulates IFNG levels by binding to and actively regulating the histone methyltransferase complex MLL/SET1 (67). The MLL/SET1 complex can turn genes on and off at lysine 4 (K4) through methylation of histone H3 (68). Therefore, IFNG-AS1 may promote the action of Th1 cytokines (IFNG, IL2) and reduce the action of Th2 cytokines (IL10, IL13) through the MLL/SET1 complex (69). These results suggest that lnc RNA IFNG-AS1 is a potential target for the treatment of IBD patients.

There is variation in the genetic locus of protein tyrosine phosphatase 2 (PTPN2) in IBD (70). PTPN2 regulates cytokine signaling by acting on a variety of phosphorylated proteins (71). Scharl et al. demonstrated that PTPN2 regulates autophagy in IECs and that there is a link between SNP rs2542151 and lower levels of PTPN2 protein in colon fibroblasts (72). SNPS at the PTPN2 locus were highly correlated with the DNA methylation level of four CpG sites downstream of PTPN2 and the expression level of the lncRNA LINC01882 downstream of these CpG sites (73). LINC01882, also known as LOC100996324 and RP11–973H3.4, is down-regulated in anti-CD3/CD28-activated CD4+ T cells and can inhibit T cell activation by inhibiting the expression of ZEB1, KLF12 and MAP2K4 to suppress IL-2 expression (73). It has been found that LINC01882 is involved in some autoimmune diseases including IBD. For example, LINC01882 ameliorates acute graft-versus-host disease (aGVHD) via skewing CD4+ T cell differentiation toward Treg cells (74). They also found that LINC01882 promoted Treg differentiation in CD4+ T cells via sponge let-7b-5p (74). This is a target for induction of immune tolerance, which offers the possibility of an effective therapeutic target for patients with aGVHD. LINC01882 is involved in IL-2 expression, which affects the immune response, homeostasis, and differentiation of a variety of lymphocytes, including Tregs. Changes in the number of Tregs contribute to the progression of autoimmune diseases. At present, there are few studies on LINC01882 and IBD, and their relationship still needs to be further explored.

Tregs are important for maintaining intestinal self-tolerance, and their dysfunction is associated with CD and its degree of inflammation (65). Forkhead box P3 (Foxp3) is a major transcription factor controlling the development and function of Tregs. Kim et al. identified a T-cell receptor response enhancer in the first intron of Foxp3 that was dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island (75). Therefore, the generation, development, and function of Tregs are dependent on Foxp3 and CREB. Some studies have found that lncRNA DQ786243 and CREB are significantly overexpressed in patients with active CD compared with healthy people or patients with inactive CD (17). However, Foxp3 expression was decreased in inactive CD patients, and there was no significant difference between active CD and healthy people (17). DQ786243 may have a significant effect on the regulation of CREB and Foxp3 genes. Qiao et al. found that DQ786243 could promote CREB and Foxp3 expression and CREB phosphorylation after transfection in Jurkat cells (17). In addition, DQ786243, CREB and Foxp3 mRNAs were all associated with C-reactive protein (CRP), an important serum biomarker of inflammation (17). All these findings suggest that lncRNA DQ786243 is associated with CD, and DQ786243 may regulate the function of Tregs by affecting the expression levels of CREB and Foxp3.

Maternally expressed 3(MEG3), a currently concerned lncRNA, has been shown to have anti-inflammatory effects in a variety of inflammatory diseases (76, 77). Wang et al. found that lncRNA-MEG3 was expressed at low levels in a H2O2 -induced Caco-2 cell model and TNBS-induced ulcerative colitis in young rats (78). They injected the lncRNA MEG3 overexpression vector into the UC rat model and found that inflammatory cytokine levels and ROS release were significantly decreased, and IL-10 expression was significantly increased (78). IL-10 is a single-chain glycoprotein that can be produced by adaptive and innate immune cells. It has anti-inflammatory and immunomodulatory effects and can regulate the role of other cytokines in immune and inflammatory diseases. They also found that lncRNA MEG3 may inhibit the release of inflammatory cytokines and ROS by stimulating IL-10 expression (78). Their study similarly confirmed that pyroptosis and apoptosis can be triggered during the pathogenesis of UC, and lncRNA MEG3 can prevent both types of cell death (78). Some studies have reported that miR-98–5p can directly target IL-10 (79). Later they confirmed that lncRNA MEG3 positively regulates IL-10 expression. In addition, knockdown of miR-98–5p was previously shown to alleviate the symptoms of IBD (80). More importantly, the elevation of lncRNA MEG3 inhibited the upregulation of miR-985p expression and promoted the expression of IL-10 by sponging miR-98–5p in UC rats (78). In conclusion, lncRNA-MEG3 can alleviate UC by up-regulating miR-98–5p-loaded IL-10 expression, providing a new potential therapeutic strategy for UC treatment.

LUCAT1 has previously been identified as a negative feedback regulator of type I interferon (IFN) and inflammatory cytokine expression in human bone marrow cells ( Figure 6 ) (81). It was originally found in lung epithelial cells. Vierbuchen et al. identified the protein important in mRNA processing and alternative splicing as the LUCAT1 binding protein (82). These binding proteins include heterogeneous nuclear ribonucleoprotein (HNRNP) C, M and A2B1, which participate in mRNA splicing and processing, including an mRNA of anti-inflammatory gene NR4A2. At the same time, they found that cells lacking LUCAT1 altered splicing of selected immune genes. For example, splicing of nuclear receptor 4A2 (NR4A2) was particularly affected by lipopolysaccharide (LPS) stimulation (82). In cells lacking LUCAT1, the expression of NR4A2 is reduced and delayed, and the expression of immune genes is elevated in NR4A2-deficient cells. These observations suggest that LUCAT1 is induced to control the splicing and stability of NR4A2, which is partly responsible for the anti-inflammatory effects of LUCAT1. They also found that LUCAT1 levels were elevated in patients with chronic obstructive pulmonary disease (COPD) or IBD and that LUCAT1 levels correlated with disease severity (82). Another study revealed lnc RNA-mediated downregulation of innate immunity and inflammatory responses in the SARS-CoV-2 vaccination breakthrough infections (83). They found that LUCAT1 regulates NF-KB-dependent genes by regulating the JAK-STAT pathway in addition to IFN genes (83). In summary, LUCAT1 plays an important role in the regulation of inflammatory diseases. Therefore, LUCAT1 may be used as a potential biomarker and therapeutic target. It is necessary to conduct more studies on the role of LUCAT1 in inflammatory diseases, which can provide new treatment ideas for inflammatory diseases.

HIF1A-AS2 is the Roseburia intestinalis flagellin-induced lncRNA in gut epithelium. Quan et al. found that silencing HIF1A-AS2 abrogated the anti-inflammatory effect mediated by intestinal flagellin (84). They also found that HIF1A-AS2 inhibited inflammation by inactivating the NF-ĸB/JNK pathway and reducing the expression of cytokines such as TNF-a, IL-1b, IL-6, and IL-12 (84). Moreover, knockdown of HIF1A-AS2 significantly increased p65 and Jnk phosphorylation and fully abrogated flagellin-mediated anti-inflammatory effects in vivo. Their study provides new insights into the mechanisms by which lncrnas regulate flagellin-mediated resolution of colonic inflammation. Upstream stimulatory factor 1 (USF1) is a class of transcription factors related to coronary artery disease (CAD) (85), which can be used as a mediator to participate in the anti-inflammatory strategy for the treatment of acute lung injury (86). Activating transcription factor 2 (ATF2), a member of basic leucine zipper proteins, is widely expressed in various tissues and participates in inflammatory responses (87). Li et al. demonstrated the proinflammatory role of lncRNA HIF1A-AS2 in atherosclerosis (88). Down-regulation of lncRNA HIF1A-AS2 inhibits atherosclerotic inflammation by reducing the binding of USF1 to the promoter region of ATF2, thereby reducing the expression of ATF2 (88). Therefore, HIF1A-AS2 may be a negative regulator of intestinal inflammation and may be a new target for the treatment of IBD in the future.

LncRNA ANRIL, located on chromosome 9p21, shows significant down-regulation in IBD disease (89). Qiao et al. explored the role of ANRIL and its possible mechanistic studies after stimulating UC to cause inflammatory injury by lipopolysaccharide (LPS) treated human embryonic cells (FHCs) (90). They found that inhibition of ANRIL could negatively regulate miR-323b-5p to alleviate LPS-induced FHCs damage (90). In addition, their results also indicated that miR-323b-5p negatively regulated TLR4 expression (90). TLR4 was the target of miR-323b-5p. It has been shown to be upregulated in UC, causing inflammation and promoting UC development (91). Knockdown of TLR4 reversed the effect of miR-323b-5p in inhibiting LPS-induced injury in FHCs (90). TRL4 is the only TLR capable of activating the MyD88-dependent signaling pathway (92). MyD88 is not only a key downstream signaling ligand of TLR4 receptor complex, but also an important adaptor protein of NF-kB signaling pathway (93). NF-kB pathway is a central mediator involved in immune and inflammatory responses (94), which can play a therapeutic role in UC. Therefore, ANRIL may affect the development of UC by regulating the miR-323b-5p/TLR4/MyD88/NF-κB pathway, which provides new ideas for the treatment of UC in the future. Li et al. found many lncrnas differentially expressed in CD mucosa, indicating that these lncRNAs were all involved in the immune response (95). For example, lncRNA ATG induces stress and apoptotic protease activation in intestinal epithelial cells in the inflammatory environment of CD (96). Caspase-3-mediated cleavage of ATG16L1 is increased, leading to abnormal autophagy in intestinal epithelial cells (96). When the activity of DDX5 in Th17 cells is increased, a large number of lncRNA Rmrp is decomposed, which would bind to RORγ-t, thus causing the latter to undergo nuclear transport, acting on the corresponding promoter, and promoting the development of Th17. Th17 maturation has a protective effect on CD (42, 97, 98). In addition, ENST0000487539_1.1 levels are increased in the serum of CD patients, and they can regulate Treg cell function by regulating Foxp3 levels. They also hypothesized that these lncRNAs might be involved in the regulation of intestinal mucosal function through the genetic network of lncRNA-miRNA/TFs-mRNAs (95).