Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

Molle, Céline; Zhang, Tong; Lendonck, Laure Ysebrant de; Gueydan, Cyril; Andrianne, Mathieu; Sherer, Félicie; Simaeys, Gaëtan Van; Blackshear, Perry J.; Léo, Oberdan; Goriely, Stanislas

doi:10.1084/jem.20120707

Cited by 86 publications

(92 citation statements)

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“…For example, mice in which TTP was deleted only from myeloid cells did not exhibit the TTP deficiency syndrome, although they were hypersensitive to small amounts of injected LPS (11), suggesting the involvement of other cell types in the development of the syndrome. In another study, genetic ablation of genes in the IL17/IL23 axis protected mice against the development of the TTP deficiency syndrome, even in the setting of normal TNF pathways and responses (12). These recent studies highlight the concept that TTP deficiency in an intact animal affects many arms of the immune system and is a true systemic disease.…”

Section: Discussionmentioning

confidence: 90%

“…Because of the recent appreciation that TTP exerts modulatory effects on transcripts involved in several aspects of the immune system (3,4,12), we investigated the effect of the systemic TTP overexpression found in the TTPΔARE mice on the severity of certain models of immune and inflammatory diseases. We first evaluated the susceptibility of the TTPΔARE mice to collagen antibody-induced arthritis (CAIA).…”

Section: Resultsmentioning

confidence: 99%

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Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

Patial

Curtis

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate-rich elements (AREs) in the 3′-untranslated regions (3′UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3′UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases.AU-rich elements | mRNA stability | inflammation | deadenylation T ristetraprolin (TTP) is the prototype of a small family of RNA binding proteins that can bind to adenylate-uridylate (AU)-rich elements (AREs) in the 3′-UTR (3′UTR) of its target mRNAs and promote their rapid turnover (1, 2). TTP-deficient mice developed a chronic systemic inflammatory syndrome (3) that was prevented by interfering with the action of TNF (3-5). Tnf mRNA was then identified as a direct target of TTP-mediated destabilization (4, 6); its increase in stability in the TTP KO mice leads to the commensurate overproduction of TNF protein (4, 5).TTP mRNA expression exhibits a pattern characteristic of immediate-early response genes in several cell types, with low-toundetectable levels of expression under basal conditions, and a rapid and transient induction upon stimulation (4,7,8). The transient nature of this induction is largely due to the instability of the TTP mRNA itself, part of which is thought to be due to AREs located within the 3′UTR of TTP mRNA (4,8,9). Indeed, TTP has been suggested to bind to its own AREs and autoregulate its expression through a negative feedback loop (9). Although expression of TTP protein in these systems is also rapidly inducible, the protein is more stable than the mRNA after induction, often persisting at high level...

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

Patial

Curtis

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Mice that overexpress IL-23 develop a spontaneous inflammatory disease similar to ankylosing spondylitis, while mice lacking tristetraproline, which regulates Il23 mRNA stability, develop spontaneous systemic inflammation, highlighting the importance of this cytokine in regulating inflammatory T cell populations (52,53). Moreover, IL-23 is essential for the induction of the pathogenic Th17 cell gene expression profile (41).…”

Section: Il-23 and Autoimmunitymentioning

confidence: 99%

Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

Burkett¹,

Hörste²,

Kuchroo³

2015

J. Clin. Invest.

204

137

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R e v i e w S e R i e S : A u t o i m m u n i t y2 2 1 2 jci.org Volume 125 Number 6 June 2015Murine Th17 differentiation can also be induced in the absence of TGF-β1 signaling, via the combination either of IL-1β, IL-6, and IL-23 or of 42). These TGF-β1-independent Th17 cells can efficiently induce autoimmune tissue inflammation upon adoptive transfer, a trait that led to them being termed "pathogenic" Th17 cells. Additionally, they possess a gene expression profile distinct from that of "nonpathogenic" Th17 cells, which are differentiated with TGF-β1 and IL-6. These observations have led to two competing hypotheses. The first posits that IL-23 cements Th17 lineage commitment such that Th17 cells induced with TGF-β1 and IL-6 are insufficiently committed to the lineage and cannot induce autoimmune tissue inflammation. The second suggests that there are distinct subtypes of Th17 cells whose differentiation is dependent on distinct combinations of cytokines. The latter hypothesis is supported by the finding that pathogenic Th17 cells express higher levels of several Th1 lineage-associated transcripts, such as the transcription factor T-bet and IFN-γ, and have been shown to be derived from IL-17 single producers by fate mapping experiments (43,44). Similarly, an important feature of human Th17 cells, as well as those isolated from inflamed tissues in mouse models of Th17-mediated disease, is that they coproduce IL-17 with other cytokines, leading to distinct functional roles (45)(46)(47). For instance, human Th17 cells that produce both IL-10 and IL-17 preferentially respond to Staphylococcus aureus, while those that produce both IL-17 and IFN-γ recognize Candida albicans, suggesting that distinct pathogens induce distinct subtypes of Th17 cells (40). IL-17/IFN-γ coproducers have been ascribed pathogenic functions in the CNS during EAE; however, it has been difficult to reliably differentiate such cells in vitro. Repeated rounds of in vitro culture in the presence of either Th1-inducing cytokines or IL-23 can induce IL-17/IFN-γ coproducers, albeit at moderate percentages. The transcription factors T-bet, RUNX1, and RUNX3 appear to be important in the acquisition of this phenotype (48,49).Large-scale transcriptional analysis of Th17 differentiation at very high temporal resolution has begun to elucidate the molecular networks that control this process, and is a promising approach to the identification of novel regulatory molecules that control pathogenic Th17 differentiation (50, 51). In fact, Th17 development is controlled induction of this lineage. The combination of TGF-β1 and IL-6 efficiently induces IL-17-producing murine T cells in vitro and highlights the reciprocal relationship between induced Tregs, which are generated by TGF-β1 alone, and Th17 cells (19,20). A series of studies demonstrated that IL-21, a γ c -dependent cytokine, could promote the differentiation of Th17 cells (21-23). In combination with TGF-β, IL-21 induces IL-17 production from naive Th cells and promotes the expression of both RORγt, th...

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“…Ttp-knockout mice are born healthy but suffer from granulocytic hyperplasia and develop a progressive and eventually lethal pleiotropic inflammation (14). The inflammatory symptoms are reduced upon blockage of TNF or IL-23 (14,15), but it remains possible that these cytokines act together or downstream of other defects resulting from TTP deficiency. Mice with LysM-Cre-driven Ttp deletion in macrophages and neutrophils are healthy despite an increased susceptibility to endotoxin-mediated septic shock (12,16).…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

Ebner

Sedlyarov

Tasciyan

et al. 2017

Journal of Clinical Investigation

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Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

Abstract: Tristetraprolin deficiency results in enhanced IL-23 via dysregulated mRNA decay that leads to an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis.

Cited by 86 publications

References 36 publications

Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

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