Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2023.1118483 Immunology Review Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases Deng Yuanyu 1 † Shi Saiyu 1 † Luo Jie 2 Zhang Yiwei 1 Dong Hui 1 Wang Xian 3 Zhou Jian 1 Wei Zhiyuan 4 Li Jiahui 1 Xu Chen 1 Xu Shuai 5 Sun Yi 4 Ni Bing 6 Wu Yuzhang 1 Yang Di 1 * Han Chao 1 * Tian Yi 1 * 1 Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, China 2 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China 3 Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong, China 4 The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, China 5 Department of Stomatology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China 6 Department of Pathophysiology, Third Military Medical University (Army Medical University), Chongqing, China

Edited by: Cai Zhang, Shandong University, China

Reviewed by: Jorg Hermann Fritz, McGill University, Canada; Shiyang Li, Advanced Medical Research Institute, Shandong University, China

*Correspondence: Yi Tian, tianyi19831015@hotmail.com; Di Yang, 66170151@qq.com; Chao Han, hanchao151425@163.com

†These authors have contributed equally to this work

This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

 26 01 2023 2023 14 1118483 07 12 2022 16 01 2023 Copyright © 2023 Deng, Shi, Luo, Zhang, Dong, Wang, Zhou, Wei, Li, Xu, Xu, Sun, Ni, Wu, Yang, Han and Tian 2023 Deng, Shi, Luo, Zhang, Dong, Wang, Zhou, Wei, Li, Xu, Xu, Sun, Ni, Wu, Yang, Han and Tian

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Innate lymphoid cells (ILCs) are important subsets of innate immune cells that regulate mucosal immunity. ILCs include natural killer cells, innate lymphoid cells-1 (ILC1s), ILC2s, and ILC3s, which have extremely important roles in the immune system. In this review, we summarize the regulation of mRNA stability mediated through various factors in ILCs (e.g., cytokines, RNA-binding proteins, non-coding RNAs) and their roles in mediating functions in different ILC subsets. In addition, we discuss potential therapeutic targets for diseases such as chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis by regulation of mRNA stability in ILCs, which may provide novel directions for future clinical research.

 ILCs mRNA stability cytokines RBPs non-coding RNA Introduction

Innate lymphoid cells (ILCs) are located throughout the human body. Most ILCs are enriched in mucosal structures, such as skin, lung, and digestive tract, and many ILCs are found in adipose tissues and lymph nodes. ILCs play an important part in regulating immune balance in tissues, resisting pathogenic infection, and enhancing adaptive immunity (1–3). Inappropriate activation of ILCs is associated with chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis (4, 5).

For several decades, the discovery and functional studies of ILCs have enhanced understanding of immune regulation in mucosal tissues considerably. However, the development process and phylogenetic classification of ILC subsets are controversial.

ILCs are divided into two cell types: cytotoxic ILCs (which mainly represent conventional natural killer (NK) cells) and helper-like ILCs, which produce cytokines (e.g., innate lymphoid cells-1 (ILC1s), innate lymphoid cells-2 (ILC2s), innate lymphoid cells-3 (ILC3s)) (4).

NK cells and ILC1s are considered to belong in the same group of ILCs due to their secretion of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) (6). Studies have shown that ILC1s cannot control the growth or metastasis of local tumors, whereas NK cells favor tumor monitoring, possibly because transforming growth factor-β (TGF-β) signaling can convert NK cells into intermediate-ILC1s and ILC1s in the tumor microenvironment to drive immune system evasion (7, 8).

The lineage-specific transcription factor GATA binding protein-3 (GATA-3) shows high expression in ILC2s and mediates multiple functions by producing various cytokines (e.g., interleukin-4 (IL-4), IL-5, IL-9), and amphiregulin. Specifically, type-2 cytokines derived from ILC2s play a crucial part in preventing parasitic infection and inducing eosinophilic inflammation, which participates in asthma, eosinophilic esophagitis, and chronic rhinosinusitis (9).

ILC3s are a heterogeneous cell population. They include natural cytotoxic receptor (NCR) cells, which consist of lymphoid tissue inducer (LTi) cells and LTi-like cells, as well as NCR+ ILC3s. Nuclear hormone retinoic acid receptor-related orphan receptor γt (ROR γt) is required for the development and function of ILC3s, similar to T-helper type 17 (Th17) and Th22 cells (10).

Cytokines and cytokine receptors are pivotal for the function of ILCs. TGF-β acts on its receptor TGF-β receptor 2 (TGF-βR2) and attenuates IFN-γ secretion by ILC1s (11). Type-I interferons, IL-2, IL-12, IL-15, IL-18, IL-21 and their receptors positively regulate NK-cell function, whereas the interaction of IL-23, IL-27 and their receptors, may suppress or enhance NK-cell function (12). ILC2s show high expression of IL-7 receptor α (IL-7Rα), IL-33 receptor (IL-33R) and IL-17 receptor β (IL-17Rβ) (13). Therefore, epithelial cell-derived thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 can stimulate ILC2s to produce various type-2 cytokines (14). ILC3s and LTi, which express IL-23 and IL-1β receptor (IL-1βR), are stimulated by IL-23 and IL-1β to produce the signature cytokines IL-17 and IL-22 (15).

A growing body of research suggests that key mechanisms of gene regulation, including transcriptional and posttranscriptional regulation, have vital roles in the phenotype and function of ILCs. Transcriptional regulation has been studied thoroughly, but posttranscriptional regulation is much less explored. Posttranscriptional regulation is reflected mainly in the: splicing and processing of mRNA precursor heterogeneous nuclear RNA; processing and localization of mRNA from the nucleus to cytoplasm; stability or degradation of mRNA in cytoplasm. RNA editing and RNA interference also belong to the category of posttranscriptional regulation (16–20).

In recent years, several studies have revealed that mRNA stability affects the function of ILCs (21, 22). The first mechanism of mRNA degradation is exonucleolytic degradation, which removes the poly(A) tail (PAT) by exonucleases, such as the carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex or poly(A)-specific ribonuclease (PARN). mRNA can be degraded from either the 3’ end or 5’ end. Degradation from the 3’ end is associated with the binding of exosomes containing exonucleases. Degradation from the 5’ end is initiated by the formation of a complex at the 3’ end that recruits a decapping enzyme to remove the 5’ cap, and then the mRNA is degraded by 5’→3’ exonuclease. The second mechanism of mRNA degradation is endonucleolytic cleavage. For example, site-specific ribonucleases can induce internal cleavage to produce RNA fragments, which are then degraded by exonucleases. The third mechanism of mRNA degradation is nonsense-mediated degradation (NMD), which inhibits the production of aberrant proteins by eliminating abnormal mRNAs with premature termination codons (PTCs). PTCs are recognized by a protein complex that contains up-frameshift proteins during the progression of translation, which stalls the subsequent translation and recruits degradation machinery (23, 24).

Next, we focus on the role of mRNA stability regulation in the three major ILC subsets in various diseases.

 Regulation of mRNA stability can affect the antiviral, immunoregulatory, and antitumor properties of NK cells

ILC1s and NK cells mainly work together in protective responses to intracellular bacteria and viruses and in cancer immunosuppression. However, the phenotypic maturation of NK cells is dependent on the transcription factor eomesodermin (Eomes), which is highly cytotoxic (25). Under inflammatory conditions, upregulation of stress ligands in host cells can trigger activation of NK cells. In contrast, the deficiency of major histocompatibility complex type-I (MHC-I) molecules during viral infection induces inhibition of NK-cell activity (26, 27). The mRNA stability of IFN-γ, IL-10, urokinase plasminogen activator (uPA), and the receptor of uPA (uPAR) in NK cells can be regulated by many stimulating factors, such as cytokines and pathogens ( Table 1 ).

Regulation of mRNA stability in ILCs is involved in various diseases.

ILC subset Factors Target mRNA Stability Function References
NK cells Cytokines TGF-β, IL-18 IFN-γ mRNA Destabilization Prevent immune dysregulation and diseases (28, 29)
IL-2, IL-12 Stabilization Modulate immunoregulatory properties (30, 31)
IL-33 Stabilization Affect antiviral properties (32)
IL-12, IL-18 Stabilization Regulate immunity against infectious pathogens (33)
IL-2 uPA, uPAR mRNA Stabilization Affect antitumor properties (34)
Pathogen Leishmania species IL-10 mRNA Stabilization Inhibit host resistance to an intracellular pathogen (35)
ILC2 RBPs Regnase-1 Egr1, ICOS mRNA Destabilization Inhibit pulmonary fibrosis (36)
TTP IL-5 mRNA Destabilization Regulate intestinal homeostasis (37)
miRNA miRNA-155 c-Maf mRNA Destabilization Inhibit allergic rhinitis (38)
miRNA-155-5p TP53INP1 mRNA Destabilization (39)
ILC3 CircRNA circZbtb20 Nr4a1 mRNA Stabilization Decrease susceptibilities to bacterial infection (40)
Cytokines regulate the stability of IFN-γ mRNA through protein kinase C and p38 mitogen-activated protein kinases signaling pathways in NK cells

IFN-γ plays a vital part in regulating the immune response. IFN-γ produced by NK cells has antiviral, immunoregulatory, and antitumor properties (41, 42). The antitumor function of NK cells mediated by IFN-γ can induce apoptosis, tumor dormancy, and immunoediting in tumor cells that are related to the relapse and progression of tumors (43, 44). Recently, several studies have shown that PKC and p38 MAPK signaling pathways have critical roles in the cytokine-mediated stability of IFN-γ mRNA ( Figure 1 ).

Regulation of the stability of IFN-γ mRNA in NK cells through p38 MAPK and PKC signal-transduction pathways. For clarity, these posttranscriptional regulators are not necessarily placed at the correct cell site. IL-12 and IL-18 can enhance the stability of IFN-γ mRNA in NK cells through the p38 MAPK pathway, which may phosphorylate unknown RBPs to result in decreased RNA-binding affinity and then decreased deadenylation. TGF-β inhibits the stability of IL-18-induced IFN-γ mRNA. IL-18 may inhibit TTP mRNA and affect the stability of IFN-γ mRNA through the p38 MAPK pathway, which may phosphorylate TTP. This phosphorylation results in the decreased RNA-binding affinity of TTP, which can trigger deadenylation of IFN-γ mRNA by recruiting cytoplasmic deadenylase. However, TGF-β can upregulate TTP transcription specifically through the Smad pathway. Smad proteins downstream of TGF-β receptors can mediate a stimulatory effect by binding the SBE of the TTP promoter (45), thereby repressing expression of IL-18-induced IFN-γ mRNA through TTP-induced destabilization. A similar TTP-related mechanism may be found in IL-33-stimulated NK cells. IL-2 and IL-12 may affect the stability of cytoplasmic IFN-γ mRNA and stability of the nuclear-processed form of IFN-γ mRNA through PKC-dependent polyadenylation in NK cells. In addition, IL-12 mediates nuclear shuttling whereas IL-2 mediates nuclear retention, which may be related to AREs, but the specific mechanism requires further investigation. Solid arrows indicate confirmed mechanisms. Dashed arrows indicate possible mechanisms that need further verification. Molecular interactions and all abbreviations are explained in the text.

Many studies have shown that p38 MAPK is activated through different ways to regulate the mRNA stability of various cytokines. This regulation involves mRNA elements (e.g., adenylate-uridylate (AU)-rich elements (AREs)) and mRNA-binding proteins (46). The effect of AREs on mRNA stability relies on moieties which selectively recognize these elements and regulate the fate of mRNA via interacting with the machineries related to regulation of mRNA stability. The p38 MAPK signal-dependent phosphorylation of ARE-binding protein affects its binding to AREs and prevents degradation by recruiting the deadenylase PARN, exosome, and decapping enzyme (46). Often, the mRNA-binding protein phosphorylation affects the RNA-binding affinity or subcellular localization. For example, phosphorylated KSRP (a vital factor for ARE-mediated mRNA decay) on T692 by p38 MAPK reduces its affinity toward AREs, resulting in increased stability of transcripts containing ARE (47). Also, MK2 (a kinase downstream of p38 MAPK) mediates phosphorylation at serine 52 and serine 178 to promote redistribution of zinc finger protein 36 (TTP) from nucleus to cytoplasm in HeLa cells (48). Furthermore, the phosphorylation of mRNA-binding proteins can alter interaction among mRNA-binding proteins and change scaffolding properties for mRNA-modifying enzymes, such as polyadenylases, deadenylases, poly (A) binding proteins (PABP), decapping enzymes, endonucleases, exonucleases, and exosome proteins. In many cases, the phenomenon results in mRNA stabilization (46). In addition to AREs, the p38 MAPK signaling pathway can regulate mRNA stability through the 3′ untranslated region (3′UTR), which has a critical role in regulation of mRNA stability (49).

IL-12 and IL-18

IL-12, produced primarily by monocytes and macrophages, stimulates the growth of NK cells (at least in part) and Th1 cells through binding to its receptor on these cells (50). The effect elicited by IL-18 resembles the effect of IL-12, possibly because they synergize (51). In NK cells stimulated by IL-12 plus IL-18, IFN-γ mRNA was shown to be destabilized potently by a specific inhibitor of p38 MAPK, and its half-life decreased, which demonstrated that IL-12 plus IL-18 could enhance the stability of IFN-γ mRNA rapidly through the p38 MAPK signaling pathway and, thus, increase the expression of IFN-γ in NK cells (33). Simultaneously, destabilization of IFN-γ mRNA by inhibitors of p38 was accompanied by shortening of the PAT (52), thereby illustrating that regulation of the stability of IFN-γ mRNA might be related to the PAT. Some studies have shown that IL-12- plus IL-18-induced IFN-γ stabilization might be caused by blocking of mRNA deadenylation (52–54), but the specific RBP acting on the IFN-γ mRNA has not been identified.

 IL-33

IL-33, a nuclear cytokine from the IL-1 family, is expressed abundantly in epithelial, endothelial, and fibroblast-like cells (55). Upon tissue damage, it acts as an alarm signal (alarmin) to alert immune cells expressing IL-1 receptor like 1 (IL-1RL1), such as tissue-resident immunological cells, including regulatory T cells (Tregs), mast cells, ILC2s, NK cells and macrophages (55). Ochayon et al. measured the phosphorylation and downstream targets of p38 MAPK in NK cells through flow cytometry (FCM) and treated the culture with actinomycin D to inhibit production of nascent RNA, thereby permitting the decay measurement of existing IFN-γ transcripts in NK cells. They revealed that IL-33 could enhance the mRNA stability of IFN-γ and then promote IFN-γ expression, which was mediated by rapid induction of phosphorylation of the activated protein-1-dependent p38 MAPK signaling pathway (32). Posttranscriptional regulation of cytokines by MK2/3 in macrophages was mediated by TTP, which could regulate the stability of AREs containing mRNAs (56). We have hypothesized analogous underlying mechanisms in NK cells, which need to be investigated further.

MK2 phosphorylation regulates inflammation (57, 58). However, only a partial inhibitory effect on IL-12/IL-33 synergistic interactions after suppressing MK2 has been noted compared with the inhibition of p38 MAPK (32). These findings imply that other p38 MAPK-induced mediators, such as activation transcription factor 2 (ATF2), may also be critical for the enhancement of IL-33 effect, and additional studies focusing on correlation with regulation of mRNA stability are needed (32).

 TGF-β and IL-18

TGF-β has three known family members (TGF-β1, TGF-β2 and TGF-β3) in mammals that can regulate various physiological processes (59). Inoue et al. reported that TGF-β1 inhibited IL-18-induced IFN-γ production and antiviral activity by downregulating the stability of IFN-γ mRNA in a mouse line of NK cells (LNK5E6) (28). They also found that the IFN-γ mRNA stability was regulated by destabilizing elements in the IFN-γ mRNA 3′UTR, particularly AREs in 5’ half of the 3′UTR (29). However, the underlying mechanism of stability regulation is incompletely understood. A similar mechanism has been reported in a human myelomonocytic cell line (KG-1). IL-18 inhibited TTP mRNA and led TTP phosphorylation by inducing p38 MAPK-activated MK2, and then localized TTP to the cytoplasm to interact with ARE. Phosphorylated TTP lost its ability which could trigger the deadenylation of IFN-γ mRNA due to blockade of the recruitment of cytoplasmic deadenylases (60, 61). However, TGF-β could induce multiple cell types to upregulate TTP transcription through the Smad pathway. Smad proteins, downstream of TGF-βRs, can mediate a stimulatory effect by binding to the Smad-binding element (SBE) of the TTP promoter (45), thereby repressing IL-18-induced IFN-γ mRNA expression through TTP-induced destabilization (62, 63).

 IL-2 and IL-12

IL-2 and IL-12 strongly regulate IFN-γ expression (30, 31). Ye et al. demonstrated that in NK3.3 cells (a human NK cell line dependent on IL-2), the increase of IFN-γ protein induced by stimulation of IL-2 plus IL-12 was due largely to the enhanced stability of cytoplasmic IFN-γ mRNA. Additional studies revealed that IFN-γ mRNA induced by IL-2 plus IL-12 in NK cells required PKC activation, showing that regulation of the stability of IFN-γ mRNA by IL-2 plus IL-12 might be mediated by the PKC pathway (30). Hodge et al. showed a novel manner of posttranscriptional regulation in IFN-γ expression: the role of IL-2, IL-12 and polyadenylation was related to mRNA stability (31, 64–67). IL-2 plus IL-12 appeared to make the processed form of mRNA more stable, and then promoted increased nucleocytoplasmic shuttling of mature IFN-γ mRNA (31). However, compared with IL-2- plus IL-12-induced cytoplasmic stabilization, IL-12 had nuclear effects which resulted in increased accumulation of the precursor and processed IFN-γ mRNA. Interestingly, IL-2 could overcome the IL-12-induced nuclear-retention of IFN-γ mRNA, which resulted in rapid shuttling of IFN-γ mRNA. In other words, the IL-12-induced nuclear retention of IFN-γ mRNA prevailed until receiving IL-2 stimulation, which mediated transcription-independent movement of nuclear IFN-γ mRNA. Ultimately, the increased expression of IFN-γ mRNA in cytoplasm resulted in the enhanced synthesis and secretion of IFN-γ protein from NK92 cells (31). Nuclear retention of IFN-γ mRNA might be mediated by a specific mRNA element, such as the AREs of IFN-γ mRNA in its 3′UTR. This speculation was supported by the observation that a sequence-mediated nuclear mRNA-retention element (which was identified in the U2AF mRNA) could prevent transport of nucleocytoplasmic mRNA (68). However, the role of AREs in mRNA nuclear retention has not yet been determined, and needs further investigation.

 Infection with <italic>Leishmania</italic> parasites alters the stability of IL-10 mRNA to affect anti-inflammation mechanisms in NK cells

IL-10 is an anti-inflammatory cytokine and its expression is controlled by some transcription factors, such as specificity protein 1 (Sp-1) and Sp-3 (69). IL-10 can contribute to the development of many diseases (70–72). NK cells can also differentiate to produce IL-10 and may have regulatory activity (73). IL-10 mRNA 3 ‘UTR has multiple copies of the potential mRNA destabilization motif (AUUUA), which are associated with the regulation of mRNA stability and located in three potential regulatory regions (AU1, AU2, AU3) (74, 75). Maroof et al. described a posttranscriptional mechanism of regulation involving IL-10 expression that induced long-term activation in vivo after infection with Leishmania parasites and enhanced stability of IL-10 mRNA in NK cells. Those actions enhanced the production of IL-10 protein and the inhibitory function of NK cells to diminish host resistance to an intracellular pathogen (35). The specific regulatory mechanism of stability of IL-10 mRNA has not been reported in NK cells, but a precedent has been found in macrophages that control IL-10 secretion. Specifically, upon macrophage activation, IL-10 transcription was upregulated through phorbol 12-myristate 13-acetate response elements located in the promoter of IL-10. Then, the degradation of IL-10 mRNA was inhibited, which was related to these three regulatory regions in the IL-10 mRNA 3’UTR (74, 75). Recently, several ARE-binding proteins (76–80) and ARE-recognizing proteasomes (81) have been reported, which might be involved in the destabilization of IL-10 mRNA through regulation of AU2 in macrophages. However, the molecular mechanism underlying infection by Leishmania species-induced enhancement of the stability of IL-10 mRNA in NK cells is not clear, and additional studies are needed to determine if similar mechanisms exist in NK cells.

 IL-2 modulates the accumulation, metastasis, and cytotoxicity of NK cells by regulating the stability of uPA/uPAR mRNA in NK cells

uPA and uPAR have major roles in NK cell-mediated decay of the extracellular matrix (82, 83). These roles may be related to the accumulation, metastasis, and cytotoxicity of NK cells (84). Recently, via Matrigel™-based studies, an increase in the number of invading NK cells has been reported after IL-2 stimulation, and this invasion has been demonstrated to employ the uPA system (84, 85). Al-Atrash et al. revealed that IL-2 upregulated expression of uPA and uPAR in NK cells, and that the half-life of uPA mRNA in IL-2-treated cells was slightly longer than that in unstimulated cells. Therefore, the enhanced stability of uPA mRNA might be a contributory factor to its expression upregulation (34). In lung fibroblasts as well as in epithelial, carcinoma, and mesothelial cells, the expression regulation of uPA and uPAR has been shown to occur at a posttranscriptional level, which was mediated by the interaction of a 30-kD RBP to the uPA mRNA 3′UTR (86) and a 50-kD RBP to the coding region of uPAR mRNA (87–89), which resulted in destabilization of the binding of uPA/uPAR mRNA. Moreover, the expression of uPAR RBP decreased, which might contribute to the increase of uPAR mRNA after IL-2 treatment in YT cells (a NK-like lymphoid cell line). However, other mechanisms cannot be excluded, such as structural modification of uPAR RBP. Therefore, Al-Atrash et al. indicated that the mRNA stability of uPAR in IL-2-stimulated YT cells appeared to be regulated (at least partly) by destabilizing RBPs interactions. Under such conditions, modifying the stability of uPA mRNA in NK cells could enhance the infiltration of NK cells into tumors, thus destroying tumors more effectively (90–93). Therefore, increasing invasiveness by NK cells before administration of NK cells in cancer immunotherapy by upregulating regulation of uPA and/or uPAR expression may increase infiltration into tumors and eradication of tumor cells by NK cells.

 Regulation of mRNA stability can affect pulmonary fibrosis, allergic rhinitis, and the intestinal homeostasis of ILC2s

ILC2s play a vital part in preventing parasitic infection and inducing eosinophil inflammation by secreting type-2 cytokines. ILC2s are involved in regulating intestinal homeostasis and the development of diseases, such as pulmonary fibrosis and allergic rhinitis (94–99). In addition, an increasing number of studies have revealed that RBPs and microRNAs (miRNAs) have crucial roles in regulating the homeostasis of ILC2s through control of mRNA stability.

The next part of this review focuses on the notion that mRNA stability of early growth response 1 (Egr1), inducible costimulator (ICOS), IL-5, c-Maf and tumor protein p53-induced nuclear protein (TP53INP1) in ILC2s can be regulated by RBPs and miRNAs ( Table 1 ).

RBPs maintain ILC2s homeostasis by regulating the mRNA stability of Egr1, ICOS, and IL-5 Regnase-1

Regnase-1 encoded by MCPIP1 (ZC3H12A) inhibits gene expression through mRNA degradation (100, 101). Yoshinari et al. screened the binding sites of transcription factors for upregulated genes related to “pulmonary fibrosis” in Comparative Toxicogenomics Database. They identified a set of transcription factors that may regulate gene expressions associated with pulmonary fibrosis. Among the identified transcription factors, regnase-1 deficiency resulted in >60-fold higher expression of Egr1 (which enhances the transcription of various fibrosis-associated genes (102, 103)) in ILC2s. The overexpression of wild-type (WT) regnase-1 rather than mutated regnase-1 inhibited the luciferase reporter harboring the 3′UTR of Egr1, suggesting that the mRNA of Egr1 was degraded by regnase-1. In addition to Egr1, ICOS has been reported that it isto be positively associated with the amount of ILC2s in the blood of patients with idiopathic pulmonary fibrosis (36). Maazi et al. found that ICOS had an important role in the survival of ILC2s and cytokine production through the IL-2 and signal transducer and activator of transcription 5 (STAT5) pathway (104). Yoshinari et al. found that ICOS expression was upregulated significantly in ILC2s deficient in regnase-1 (36). Uehata et al. showed that regnase-1 degraded ICOS mRNA directly through the 3′UTR in T cells (105): additional studies needed to be ascertained if similar mechanisms exist in ILC2s. Taken together, those data suggested that the posttranscriptional regulation of Egr1 and ICOS by regnase-1 in ILC2s suppressed the pro-fibrotic function of ILC2s in lung. Therefore, regnase-1 is regarded as a crucial posttranscriptional regulator for the pro-fibrotic function of ILC2s in mice and humans, and its regulatory mechanism for Egr1 and ICOS may provide novel therapeutic strategies for idiopathic pulmonary fibrosis. However, further studies are needed of all the transcriptional and posttranscriptional gene-regulation networks that can regulate pulmonary fibrosis by ILC2s (36).

 TTP

The tristetraprolin family, which includes TTP, zinc finger protein 36 like 1, and zinc finger protein 36 like 2, has critical roles in posttranscriptional regulation, especially for regulation of mRNA stability (106). TTP (also known as TIS11, Zfp36, and Nup475) contains two zinc-finger domains that have a crucial role in the posttranscriptional regulation of inflammation (107–109). Hikichi et al. overexpressed TTP significantly using a retroviral vector and found that the production of IL-5 was inhibited in IL-2- and IL-33-stimulated ILC2s. They assessed the stability of IL-5 mRNA and found that TTP overexpression could enhance mRNA degradation. Those results suggested that TTP regulated IL-5 expression in ILC2s through mRNA degradation (37). Hikichi et al. undertook luciferase reporter assays with IL-5 3′UTRs. They created three constructs through mutation of different AREs in the IL-5 3′UTR and carried out a reporter experiment. Those results showed that TTP regulated IL-5 expression directly by binding to the IL-5 mRNA △ ARE 5-7 sequence, which led to a reduction in the stability and expression of IL-5 mRNA. Studies have demonstrated that the mechanism of mRNA degradation by TTP involves the C-terminal domain recruiting a deadenylase to remove the PAT (109).

IL-5, derived from ILC2s, has been reported to maintain steady-state eosinophils in small intestine (110). Hence, the mucosal barrier can be protected by these homeostatic eosinophils in the small intestine through supporting immunoglobulin-A secretion from plasma cells (111, 112). Hikichi et al. analyzed the eosinophil number in small intestine and lungs of Zfp36-deficient mice. In accordance with the increased number of ILC2s, the accumulation of eosinophils was significantly enhanced in small intestine of Zfp36-deficient mice. Those results indicated that TTP regulated eosinophil number via an appropriate production of ILC2s-derived IL-5, thereby contributing to intestinal homeostasis (37).

 miRNA affects allergic rhinitis by regulating the stability of c-Maf mRNA and TP53INP1 mRNA in ILC2s

miRNAs, as one of small and noncoding RNAs, regulate gene expression at posttranscriptional level specifically (113). miRNAs can load into the RNA-induced silencing complex (RISC) and then bind to the 3′UTR of target mRNAs, which results in the degradation or translational inhibition of mRNA (114).

miRNA-155 is a key regulator for ILC2s and NK cells, impacting their development and functions (115–117). Through database analysis with bioinformatics software (TargetScan, PicTar, miRanda) and luciferase reporter assays, Zhu et al. suggested that miRNA-155 targeted WT c-Maf 3′UTR. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), Zhu et al. determined the roles of miRNA-155 in the expression of c-Maf and Th2 cytokines in ILC2s. miRNA-155 overexpression inhibited the expression of c-Maf mRNA and protein significantly, and increased Th2 cytokines expression including IL-4, IL-5, IL-9 and IL-13, in ILC2s. Those results indicated that miRNA-155 decreased the mRNA and protein expression of c-Maf and promoted expression of Th2 cytokines in ILC2s by binding to the c-Maf mRNA 3′UTR (38). In allergic rhinitis, increased activity of ILC2s and release of Th2 cytokines have been considered to be the main causes of disease aggravation (38). Reduced c-Maf expression in the nasal mucosa of mice and patients with allergic rhinitis was recovered significantly by administration of miRNA-155 antagomir, suggesting that miRNA-155 might be a therapeutic target for allergic diseases (38). However, whether miRNA-155 affects the secretion of Th2 cytokines in ILC2s through regulating the stability of c-Maf mRNA is not known.

Zhu et al. demonstrated that there was a target RNA of miRNA-155-5p in ILC2s: TP53INP1 (a tumor-suppressor protein). miRNA-155-5p could downregulate the stability of TP53INP1 mRNA and expression of TP53INP1 through binding to a specific sequence (AGCAUUAA) in TP53INP1 mRNA 3’UTR. TP53INP1 is negatively correlated with miRNA-155-5p. In contrast, TP53INP1 could inhibit the production of Th2 cytokines in ILC2s and promote the production of Th1 cytokines and ILC2s apoptosis. miRNA-155-5p showed high expression in allergic rhinitis. Studies have demonstrated that TP53INP1 may have an anti-inflammatory role because it can inhibit the nuclear factor-κ B (NF-κB) signaling pathway in patients with allergic rhinitis, but the specific mechanism is largely unknown (39).

 Regulation of mRNA stability can modulate susceptibilities to bacterial infection of ILC3s

ILC3s have critical roles in innate immunity and gut homeostasis (118). In recent years, mRNA stability in ILC3s has been reported to be regulated by circular RNAs (circRNAs). The section below provides evidence that the stability of Nr4a1 mRNA in ILC3s can be regulated by circRNAs ( Table 1 ).

CircRNAs maintain ILC3s homeostasis by regulating the stability of Nr4a1 mRNA

circRNAs are a class of non-coding RNAs with a ring structure. They are formed by spliceosomes or nested splicing (119). Studies have shown that circRNAs can be formed in ILC3s-induced intestinal inflammation (120) and enhance the ability to resist bacterial infection (121). Liu et al. identified a circRNA (circZbtb20) through a direct interaction with the RNA pulldown assay and sequence alignment, which showed high expression of circZbtb20 in ILC3s. circZbtb20 maintained the homeostasis and function of ILC3s by enhancing the stability of Nr4a1 mRNA. Increasing numbers of studies have revealed a close correlation between Nr4a1 and regulation of the immune response. Also, Nr4a1 can initiate transcription of Notch2 to promote its expression, which is required for maintenance of the expansion and function of ILC3s. Liu et al. used the biotin-labeled linearized circZbtb20 as “bait” to conduct RNA-pulldown experiments. They found that circZbtb20 could enhance the interaction between Nr4a1 mRNA and AlkB homolog 5 (Alkbh5) (40). Alkbh5 is a demethylase for N6-methyladenosine (m6A)-modification, and is related to the mRNA stability regulation (122). M6A regulates the degradation of methylated RNA and is negatively correlated with mRNA stability (123). Liu et al. found that Alkbh5 deficiency increased m6A modification of Nr4a1 mRNA in ILC3s using single-base elongation- and ligation-based qPCR (40). Liu et al. demonstrated that the circZbtb20–Alkbh5–Nr4a1–Notch2 axis was important for the homeostasis and function regulation of ILC3s, and that the destruction of this axis increased susceptibilities to bacterial infection (40).

 Conclusions and perspectives

ILCs are a fascinating cell population and have important roles in several diseases. In the past decade, there has been an explosion of knowledge surrounding the identification, development plans, and functionality of ILCs.

Here, we summarized the current findings of the regulation of mRNA stability on ILCs function. In particular, we focused on the effects of RBP on regulation of mRNA stability in ILCs. First, even though multiple cytokines (e.g., IL-12, IL-18) have been shown to have important regulatory roles on ILC1s function, mRNA stability-related RBPs in ILC1s have not been identified, which merits further investigation. Second, several RBPs have been shown to have important roles in the regulation of ILC2s function, including regnase-1, TTP, and RNA-binding protein 3 (RBM3) (124). Specifically, regnase-1 and TTP have broad roles in mRNA stability in ILCs and other cell subsets. However, RBM3 has a potentially specific role in ILC2s because studies have shown that RBM3 deficiency has no effects on the numbers of NK cells, T cells, or B cells in mice. Hence, RBM3 might be an ILC2s-specific RBP in immune cells (124). Third, a few studies have reported that circRNAs can regulate downstream mRNAs stability in ILC3s indirectly (125–127). Therefore, researchers need to demonstrate the roles of mRNA stability on the regulation of ILC3s function. Taken together, evidence suggests a novel molecular mechanism for the regulation of ILCs functions, which may represent a new intervention for ILCs-related diseases such as idiopathic pulmonary fibrosis, allergic rhinitis, and cancer.

 Author contributions

Author contribution: YT, CH, DY, YW and BN: Conceived and supervised this study. YD and SS: Wrote the manuscript. JL, YZ, HD, XW, JZ, ZW, JHL, CX, SX and YS: participated in the revision of the manuscript. All authors contributed to the article and approved the submitted version.

 Funding

This work was supported by grants from the National Natural Science Foundation of China (32170887, 92269110, 32141005 and 32100708), the Chongqing Talent Program of China (cstc2022ycjh-bgzxm0020), the National College Students’ Innovation and Entrepreneurship Training Program (202190035003), and the Undergraduate Research Training Project of Third Military Medical University (Army Medical University) (2021XBK09). The funders had no role in the study design, data analyses, or decision to publish.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

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