The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPAR<i>γ</i>

Wang, Xia; Ji, Yindong; Feng, Ping; Liu, Rucheng; Li, Guosheng; Zheng, Junjie; Xue, Yaqiang; Wei, Yaxun; Ji, Chunyan; Chen, Fan; Li, Jingxin

doi:10.1002/advs.202100209

Cited by 79 publications

(57 citation statements)

References 53 publications

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“…An earlier study showed that the reader YTHDF2 was upregulated after LPS stimulation and that YTHDF2 knockdown promoted the in ammatory response in LPS-stimulated macrophages [43]. Subsequent studies con rmed that m 6 A modi cation regulated M1/M2 polarization and cholesterol e ux [24,29,41,42]. However, the function of Mettl14 in macrophages in atherosclerosis has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

Yang

Ran

et al. 2021

Preprint

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The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification “writer” Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

Yang

Ran

et al. 2021

Preprint

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“…The stability of HPSE was analyzed using Actinomycin D according to a previous report with some modifications [ 25 ]. In brief, HaCaT cells transfected with sh-NC or sh-IGF2BP2 were treated with 2 μg/mL Actinomycin D (Sigma-Aldrich) for 0, 1, 2, or 4 h. Then, total RNA was isolated, and HPSE mRNA level was examined using qRT-PCR.…”

Section: Methodsmentioning

confidence: 99%

“…The interaction between IGF2BP2 and HPSE was analyzed by RIP assay following a previous report with some modifications [ 25 ]. RIP analysis was performed with a Magna RIP kit (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor 2 mRNA binding protein 2 regulates proliferation, migration, and angiogenesis of keratinocytes by modulating heparanase stability

Zhi¹,

Li²,

Kong³

et al. 2021

Bioengineered

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Wound healing is related to proliferation, migration, and angiogenesis of keratinocytes. Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) is an important N6-methyladenosine (m6A) reader, which is involved in multiple processes, including wound healing. However, the function and mechanism of IGF2BP2 in keratinocyte processes are largely uncertain. In the present study, expression levels of IGF2BP2 and heparanase (HPSE) were detected by quantitative reverse transcription polymerase chain reaction and western blotting assays. Cell proliferation was investigated by cell counting kit-8 (CCK-8) analysis. Cell migration was determined through wound healing assay. Angiogenesis was measured by tube formation assay and vascular endothelial growth factor (VEGF) level using enzyme linked immunosorbent assay (ELISA). The interaction between IGF2BP2 and HPSE was analyzed by RNA immunoprecipitation, pull-down and luciferase reporter analyses. The results showed that IGF2BP2 expression was enhanced in wound healing. IGF2BP2 downregulation constrained HaCaT cell proliferation, migration, and angiogenesis. IGF2BP2 knockdown decreased HPSE expression. IGF2BP2 could regulate HPSE stability by binding with 3ʹ untranslated region (UTR) of HPSE. HPSE upregulation attenuated silencing IGF2BP2-mediated suppression of proliferation, migration, and angiogenesis. As a conclusion, IGF2BP2 knockdown repressed proliferation, migration, and angiogenesis of HaCaT cells by decreasing HPSE stability.

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“…The depletion of IGF2BP2 also enhanced the M1 phenotype. Additionally, it also has a mediator function on PPARγ involved in the differentiation of M2 macrophages ( Wang et al, 2021b ). Bechara et al demonstrated the unexpected involvement of m6A modification in regulating C/EBPβ and C/EBPδ under autoimmune inflammation.…”

Section: N6-methyladenosine Modification In Mediating Inflammation Responsesmentioning

confidence: 99%

Novel Insights Into the Potential Mechanisms of N6-Methyladenosine RNA Modification on Sepsis-Induced Cardiovascular Dysfunction: An Update Summary on Direct and Indirect Evidences

Wang

Peng

et al. 2021

Front. Cell Dev. Biol.

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Sepsis is a life-threatening organ dysfunction caused by a host’s dysfunctional response to infection. As is known to all, septic heart disease occurs because pathogens invading the blood stimulate the activation of endothelial cells, causing a large number of white blood cells to accumulate and trigger an immune response. However, in severe sepsis, the hematopoietic system is inhibited, and there will also be a decline in white blood cells, at which time the autoimmune system will also be suppressed. During the immune response, a large number of inflammatory factors are released into cells to participate in the inflammatory process, which ultimately damages cardiac myocytes and leads to impaired cardiac function. N6-methyladenosine (m6A) is a common RNA modification in mRNA and non-coding RNA that affects RNA splicing, translation, stability, and epigenetic effects of some non-coding RNAs. A large number of emerging evidences demonstrated m6A modification had been involved in multiple biological processes, especially for sepsis and immune disorders. Unfortunately, there are limited results provided to analyze the association between m6A modification and sepsis-induced cardiovascular dysfunction (SICD). In this review, we firstly summarized current evidences on how m6A mediates the pathophysiological process in cardiac development and cardiomyopathy to emphasize the importance of RNA methylation in maintaining heart biogenesis and homeostasis. Then, we clarified the participants of m6A modification in extended inflammatory responses and immune system activation, which are the dominant and initial changes secondary to sepsis attack. After that, we deeply analyzed the top causes of SICD and identified the activation of inflammatory cytokines, endothelial cell dysfunction, and mitochondrial failure. Thus, the highlight of this review is that we systematically collected all the related potential mechanisms between m6A modification and SICD causes. Although there is lack of direct evidences on SICD, indirect evidences had been demonstrated case by case on every particular molecular mechanism and signal transduction, which require further explorations into the potential links among the listed mechanisms. This provides novel insights into the understanding of SICD.

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The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPARγ

Cited by 79 publications

References 53 publications

Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

Insulin-like growth factor 2 mRNA binding protein 2 regulates proliferation, migration, and angiogenesis of keratinocytes by modulating heparanase stability

Novel Insights Into the Potential Mechanisms of N6-Methyladenosine RNA Modification on Sepsis-Induced Cardiovascular Dysfunction: An Update Summary on Direct and Indirect Evidences

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