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Cytokines are critical mediators of inflammation and host immune defense. Cytokine production is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional damping of inflammatory mRNAs is mediated by a set of RNA binding proteins (RBPs) interacting with cis-elements, such as AU-rich elements (ARE) and stem-loop structures. Whereas ARE-binding proteins such as tristetraprolin and a stem-loop recognizing protein, Roquin, downregulate cytokine mRNA abundance by recruiting a CCR4-NOT deadenylase complex, another stem-loop RBP, Regnase-1, acts as an endoribonuclease, directly degrading target cytokine mRNAs. These RBPs control translation-active or -inactive mRNAs in distinct intracellular locations. The presence of various RBPs regulating mRNAs in distinct locations enables elaborate control of cytokines under inflammatory conditions. Dysregulation of cytokine mRNA decay leads to pathologies such as the development of autoimmune diseases or impaired activation of immune responses. Here we review current knowledge about the post-transcriptional regulation of immune responses by RBPs and the importance of their alteration during inflammatory pathology and autoimmunity.

RNA acts as an immunostimulatory molecule in the innate immune system to activate nucleic acid sensors. It functions as an intermediate, conveying genetic information to control inflammatory responses. A key mechanism for RNA sensing is discriminating self from non-self nucleic acids to initiate antiviral responses reliably, including the expression of type I interferon (IFN) and IFN-stimulated genes. Another important aspect of the RNA-mediated inflammatory response is posttranscriptional regulation of gene expression, where RNA-binding proteins (RBPs) have essential roles in various RNA metabolisms, including splicing, nuclear export, modification, and translation and mRNA degradation. Recent evidence suggests that the control of mRNA stability is closely involved in signal transduction and orchestrates immune responses. In this study, we review the current understanding of how RNA is sensed by host RNA sensing machinery and discuss self/non-self-discrimination in innate immunity focusing on mammalian species. Finally, we discuss how posttranscriptional regulation by RBPs shape immune reactions.

Toll-like receptor (TLR) ligands that signal via TIR-domain-containing adapter-inducing IFNβ (TRIF) activate the IκB kinase (IKK)-related kinases, TRAF associated NFκB activator (TANK)-binding kinase-1 (TBK1) and IKKε, which then phosphorylate IRF3 and induce the production of IFNβ. Here we show that TBK1 and IKKε are also activated by TLR ligands that signal via MyD88. Notably, the activation of IKKε is rapid, transient, and it precedes a more prolonged activation of TBK1. The MyD88- and TRIF-dependent signaling pathways activate the IKK-related kinases by two signaling pathways. One is mediated by the canonical IKKs, whereas the other culminates in the autoactivation of the IKK-related kinases. Once activated, TBK1/IKKε then phosphorylate and inhibit the canonical IKKs. The negative regulation of the canonical IKKs by the IKK-related kinases occurs in both the TRIF- and MyD88-dependent TLR pathways, whereas IRF3 phosphorylation is restricted to the TRIF-dependent signaling pathway. We have discovered that the activation of IKKε is abolished, the activation of TBK1 is reduced, and the interaction between the IKK-related kinases and the canonical IKKs is suppressed in TANK–/– macrophages, preventing the IKK-related kinases from negatively regulating the canonical IKKs. In contrast, IRF3 phosphorylation and IFNβ production was normal in TANK–/– macrophages. Our results demonstrate a key role for TANK in enabling the canonical IKKs and the IKK-related kinases to regulate each other, which is required to limit the strength of TLR signaling and ultimately, prevent autoimmunity.

Pre-service EFL (henceforth, L2) teacher training often involves significant emotional and motivational challenges. The present study investigates the relationship between pre-service EFL teachers’ (1) grit to become L2 teachers (PET-Grit), (2) L2 learning enjoyment (L2LE), (3) L2 teaching enjoyment (L2TE), (4) L2 learning self-efficacy (L2LSE), and (5) L2 teaching self-efficacy (L2TSE). Using Structural Equation Modeling (SEM), this study examined data from 220 Indonesian pre-service L2 teachers. The proposed model, which included the role of PET-Grit in mediating the relationship between enjoyment and self-efficacy, indicated acceptable fit indices (RMSEA = 0.045, SRMR = 0.059, CFI = 0.994, TLI = 0.993). The results of the study showed that (a) participants’ L2LE and L2TE predicted their PET-Grit, (b) participants’ PET-Grit predicted their L2SE and TSE, (c) participants’ L2TE had an indirect effect on L2TSE, and interestingly, (d) L2LE had an indirect effect on both L2LSE and L2TSE. The research underscores the role of PET-Grit in mediating the effect of enjoyment on self-efficacy. Drawing on the obtained results, the authors suggest that L2 teacher training programs take into consideration pre-service L2 teachers' enjoyment and grit to better prepare them for their teaching careers.

Posttranscriptional regulation of IL-6 has been largely uncharacterized, with the exception of the ribonuclease Regnase-1, which prevents autoimmunity by destabilizing IL-6 mRNA. Here, we identified AT-rich interactive domain-containing protein 5A (Arid5a) as a unique RNA binding protein, which stabilizes IL-6 but not TNF-α mRNA through binding to the 3′ untranslated region of IL-6 mRNA. Arid5a was enhanced in macrophages in response to LPS, IL-1β, and IL-6. Arid5a deficiency inhibited elevation of IL-6 serum level in LPS-treated mice and suppressed IL-6 levels and the development of T H17 cells in experimental autoimmune encephalomyelitis. Importantly, Arid5a inhibited the destabilizing effect of Regnase-1 on IL-6 mRNA. These results indicate that Arid5a plays an important role in promotion of inflammatory processes and autoimmune diseases.

The RIG-I–like receptors, retinoic acid inducible gene-1 (RIG-I), melanoma differentiation-associated protein 5, and laboratory of genetics and physiology-2, are cytoplasmic sensors for RNA viruses that mediate the antiviral innate immune responses. We demonstrate that really interesting new gene-finger domain- and K homology domain-containing MEX3C regulates RIG-I function. MEX3C colocalizes with RIG-I in the stress granules of virally infected cells, and its overexpression causes the lysine-63–linked ubiquitination of RIG-I and activates IFN-β promoter. Embryonic fibroblast cells, macrophages, and conventional dendritic cells derived from Mex3c-deficient mice showed defective production of type I IFN after infection with RNA viruses that are recognized by RIG-I. These results demonstrate that MEX3C is an E3 ubiquitin ligase that modifies RIG-I in stress granules and plays a critical role in eliciting antiviral immune responses.

Macrophages can be divided into two subsets, M1 and M2, which have crucial differences in their function. Akira and colleagues identify the histone demethylase Jmjd3 as a key factor in M2 development. Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infections, respectively. Jumonji domain containing-3 (Jmjd3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in the activation of macrophages. Here we show that Jmjd3 is essential for M2 macrophage polarization in response to helminth infection and chitin, though Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 (also known as Kdm6b ) is essential for proper bone marrow macrophage differentiation, and this function depends on demethylase activity of Jmjd3. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited number of genes. Among them, we identified Irf4 as encoding a key transcription factor that controls M2 macrophage polarization. Collectively, these results show that Jmjd3-mediated H3K27 demethylation is crucial for regulating M2 macrophage development leading to anti-helminth host responses.

Inflammation orchestrates a finely balanced process crucial for microorganism elimination and tissue injury protection. A multitude of immune and non-immune cells, alongside various proinflammatory cytokines and chemokines, collectively regulate this response. Central to this regulation is post-transcriptional control, governing gene expression at the mRNA level. RNA-binding proteins such as tristetraprolin, Roquin, and the Regnase family, along with RNA modifications, intricately dictate the mRNA decay of pivotal mediators and regulators in the inflammatory response. Dysregulated activity of these factors has been implicated in numerous human inflammatory diseases, underscoring the significance of post-transcriptional regulation. The increasing focus on targeting these mechanisms presents a promising therapeutic strategy for inflammatory and autoimmune diseases. This review offers an extensive overview of post-transcriptional regulation mechanisms during inflammatory responses, delving into recent advancements, their implications in human diseases, and the strides made in therapeutic exploitation.

Haematopoietic expression of the adaptor protein Trib1 is shown to be required for the presence of adipose-tissue-resident macrophages with an M2-like phenotype; Trib1 deficiency leads to aberrant expression of C/EBPα and impaired adipose tissue function. Trib1 protein role in macrophage function Macrophages are classified loosely into two types: M1 cells are immune cells active against microbial infection, and M2 cells have a broad spectrum of activities involving tissue repair, helminth infection, tumour progression and various metabolic disorders. This paper demonstrates that Tribbles homolog 1 (Trib1), an adaptor protein involved in protein degradation through interaction with COP1 ubiquitin ligase, is essential for the development of adipose-tissue-resident macrophages with an M2-like phenotype. Trib1 deficiency leads to aberrant expression of the transcription factor C/EBPα and impaired adipose tissue function. TRIB1 mutations have been implicated in metabolic disorders including atherosclerosis and hyperlipidaemia, and this work points to possible explanation of the relations between TRIB1 and metabolic disorders in humans. Macrophages consist of at least two subgroups, M1 and M2 (refs 1 , 2 , 3 ). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections 4 , 5 , M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression 6 . Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase 7 . Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism 8 , 9 , 10 . Here we show that Trib1 is critical for the differentiation of F4/80 + MR + tissue-resident macrophages—that share characteristics with M2 macrophages (which we term M2-like macrophages)—and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.

Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.