TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation

Xiao, Peipei; Li, Mingxuan; Zhou, Min; Zhao, Xuejun; Wang, Cheng; Qiu, Jinglin; Qian, Fang; Jiang, Hong; Dong, Hui-Fen; Zhou, Rui

doi:10.1172/jci.insight.149276

Cited by 17 publications

(10 citation statements)

References 38 publications

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“…These observations strongly suggest that cMoP/MP, a progenitor cell of M-MDSCs in TTPKO or cTTPKO mice, is differentiated into M-MDSCs in the periphery after mobilization into the circulation and increased in the spleen and mLN. Moreover, CCL2 has been reported as one of the targets of TTP, and when TTP is absent, CCL2 remains high throughout the body including blood, supporting the differentiation of MPs into M-MDSCs after mobilization ( 44 – 46 ). These transcriptomic data are supported by our data that CCL2 was significantly higher in the serum of cTTPKO and TTPKO mice, as well as aged WT mice.…”

Section: Discussionmentioning

confidence: 92%

Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells

et al. 2022

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Aging results in enhanced myelopoiesis, which is associated with an increased prevalence of myeloid leukemias and the production of myeloid-derived suppressor cells (MDSCs). Tristetraprolin (TTP) is an RNA binding protein that regulates immune-related cytokines and chemokines by destabilizing target mRNAs. As TTP expression is known to decrease with age in myeloid cells, we used TTP-deficient (TTPKO) mice to model aged mice to study TTP regulation in age-related myelopoiesis. Both TTPKO and myeloid-specific TTPKO (cTTPKO) mice had significant increases in both MDSC subpopulations M-MDSCs (CD11b+Ly6ChiLy6G-) and PMN-MDSCs (CD11b+Ly6CloLy6G+), as well as macrophages (CD11b+F4/80+) in the spleen and mesenteric lymph nodes; however, no quantitative changes in MDSCs were observed in the bone marrow. In contrast, gain-of-function TTP knock-in (TTPKI) mice had no change in MDSCs compared with control mice. Within the bone marrow, total granulocyte-monocyte progenitors (GMPs) and monocyte progenitors (MPs), direct antecedents of M-MDSCs, were significantly increased in both cTTPKO and TTPKO mice, but granulocyte progenitors (GPs) were significantly increased only in TTPKO mice. Transcriptomic analysis of the bone marrow myeloid cell populations revealed that the expression of CC chemokine receptor 2 (CCR2), which plays a key role in monocyte mobilization to inflammatory sites, was dramatically increased in both cTTPKO and TTPKO mice. Concurrently, the concentration of CC chemokine ligand 2 (CCL2), a major ligand of CCR2, was high in the serum of cTTPKO and TTPKO mice, suggesting that TTP impacts the mobilization of M-MDSCs from the bone marrow to inflammatory sites during aging via regulation of the CCR2-CCL2 axis. Collectively, these studies demonstrate a previously unrecognized role for TTP in regulating age-associated myelopoiesis through the expansion of specific myeloid progenitors and M-MDSCs and their recruitment to sites of injury, inflammation, or other pathologic perturbations.

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Section: Discussionmentioning

confidence: 92%

Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells

et al. 2022

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“…Interestingly, a recent report indicates that Ccl2 mRNA stability can also be negatively regulated by m 6 A through binding of the destabilizing protein TTP and the m 6 A reader YTHDF2. Moreover, TTP promoted global increases in m 6 A methylation through upregulation of the methylation machinery ( 46 ). Therefore, the impact of this RNA modification can be both positive and negative depending on context.…”

Section: Discussionmentioning

confidence: 99%

The RNA-binding protein IMP2 drives a stromal-Th17 cell circuit in autoimmune neuroinflammation

Bechara¹,

Amatya²,

Majumder³

et al. 2022

JCI Insight

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Stromal cells are emerging as key drivers of autoimmunity, partially because they produce inflammatory chemokines that orchestrate inflammation. Chemokine expression is regulated transcriptionally but also through posttranscriptional mechanisms, the specific drivers of which are still incompletely defined. CCL2 (MCP1) is a multifunctional chemokine that drives myeloid cell recruitment. During experimental autoimmune encephalomyelitis (EAE), an IL-17–driven model of multiple sclerosis, CCL2 produced by lymph node (LN) stromal cells was essential for immunopathology. Here, we showed that Ccl2 mRNA upregulation in human stromal fibroblasts in response to IL-17 required the RNA-binding protein IGF-2 mRNA-binding protein 2 (IGF2BP2, IMP2), which is expressed almost exclusively in nonhematopoietic cells. IMP2 binds directly to CCL2 mRNA, markedly extending its transcript half-life, and is thus required for efficient CCL2 secretion. Consistent with this, Imp2 −/− mice showed reduced CCL2 production in LNs during EAE, causing impairments in monocyte recruitment and Th17 cell polarization. Imp2 –/– mice were fully protected from CNS inflammation. Moreover, deletion of IMP2 after EAE onset was sufficient to mitigate disease severity. These data showed that posttranscriptional control of Ccl2 in stromal cells by IMP2 was required to permit IL-17–driven progression of EAE pathogenesis.

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“…Tristetraprolin (TTP) is an immunosuppressive protein. TTP is upregulated in acute liver failure (ALF), and the mRNA stability of C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 5 (CCL5) is weakened by m 6 A modification, thus alleviating acute liver injury ( 113 ).…”

Section: Role Of Nucleotide Methylation In the Remodeling Of The Infl...mentioning

confidence: 99%

Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease

et al. 2023

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Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by fatty infiltration of the liver. In recent years, the MAFLD incidence rate has risen and emerged as a serious public health concern. MAFLD typically progresses from the initial hepatocyte steatosis to steatohepatitis and then gradually advances to liver fibrosis, which may ultimately lead to cirrhosis and carcinogenesis. However, the potential evolutionary mechanisms still need to be clarified. Recent studies have shown that nucleotide methylation, which was directly associated with MAFLD’s inflammatory grading, lipid synthesis, and oxidative stress, plays a crucial role in the occurrence and progression of MAFLD. In this review, we highlight the regulatory function and associated mechanisms of nucleotide methylation modification in the progress of MAFLD, with a particular emphasis on its regulatory role in the inflammation of MAFLD, including the regulation of inflammation-related immune and metabolic microenvironment. Additionally, we summarize the potential value of nucleotide methylation in the diagnosis and treatment of MAFLD, intending to provide references for the future investigation of MAFLD.

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TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation

Cited by 17 publications

References 38 publications

Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells

Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells

The RNA-binding protein IMP2 drives a stromal-Th17 cell circuit in autoimmune neuroinflammation

Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease

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