Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages

Hu, Li; Yu, Yizhen; Shen, Yueyao; Huang, Huijie; Lin, Donghai; Wang, Kang; Yu, Youjia; Li, Kai; Cao, Yue; Wang, Qiang; Sun, Xiaoxuan; Qiu, Zhibing; Wang, Dong; Shen, Bin; Chen, Jingyu; Fulton, David; Ji, Yong; Wang, Jie; Chen, Feng

doi:10.1016/j.redox.2023.102638

Cited by 21 publications

(16 citation statements)

References 53 publications

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“…Of note, the base line Fulton's indices in the MISTRG mice were somewhat higher at baseline than other, non-humanized mouse models (19,26), suggesting that the absence of early lung macrophages in p14 MISTRG mice (Figure 10) may play a role in development of pulmonary hypertension. There is recent emerging evidence that alveolar macrophages may contribute to pulmonary hypertension (27). To our knowledge, the vascular findings reported here in the MISTRG model of neonatal hyperoxiainduced lung injury have not been previously reported.…”

Section: Discussionmentioning

confidence: 43%

Development of a novel humanized mouse model to study bronchopulmonary dysplasia

Birkett,

Newar,

Sharma

et al. 2023

Front. Pediatr.

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RationaleThe role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia.MethodsCord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay.ResultsAcross the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P < 0.05). Monocyte injection was associated with increased microvessel density at P14 as compared with placebo (26.7 ± 0.73 vs. 18.8 ± 1.7 vessels per lung field; P < 0.001). Pooled analysis of patients revealed that injection of monocytes from births complicated by lower GA and preeclampsia was associated with changes in alveolarization and vascularization under normoxic conditions. These differences were modified by hyperoxia. CD45+ cell count was positively correlated with plasma monocyte chemoattractant protein-1 (P < 0.001) and macrophage inflammatory protein-1β (P < 0.01). Immunohistochemical staining for human CD206 and mouse F4/80 confirmed absence of macrophages in MISTRG lungs at P14.ConclusionsDespite the inherent absence of macrophages in early stages of lung development, immunodeficient MISTRG mice revealed changes in alveolar and microvascular development induced by human monocytes. MISTRG mice exposed to neonatal hyperoxia may serve as a novel model to study isolated effects of human monocytes on alveolar and pulmonary vascular development.

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Section: Discussionmentioning

confidence: 43%

Development of a novel humanized mouse model to study bronchopulmonary dysplasia

Birkett,

Newar,

Sharma

et al. 2023

Front. Pediatr.

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“…These biological functions are inconsistent with their expression levels and the reduced expression level of RRAS. YTHDF2 can promote mRNA degradation and decrease gene expression (30)(31)(32), which may be the reason for the decrease in RRAS expression. Therefore, YTHDF2 was selected for further analysis.…”

Section: Overexpression Of Rras Suppresses Bca Cell Proliferation Mig...mentioning

confidence: 99%

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

Chen

Wang

et al. 2023

Oncol Rep

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The present study aimed to explore the potential roles of the methyltransferase-like 3 (METTL3)-mediated methylation of RAS related (RRAS) mRNA in the tumorigenesis and development of bladder cancer (BCa). For this purpose, the relative expression levels of METTL3 in BCa specimens and cell lines were measured using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. The association between the METTL3 expression level and the clinical characteristics of patients with BCa was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis databases. Cellular experiments were performed to confirm the effects of METTL3 on the proliferative, migratory and invasive capacities of BCa cells. RT-qPCR, western blot analysis, methylated RNA immunoprecipitation (MeRIP)-qPCR and dual-luciferase report assays were utilized to verify the METTL3/RRAS/YTH N 6 -methyladenosine (m6A) RNA binding protein 2 (YTHDF2) regulatory axis in BCa. The results revealed that METTL3 expression was markedly increased in BCa specimens and cell lines, and was associated with poor clinical characteristics of patients with BCa. In vitro and in vivo assays demonstrated that the silencing of METTL3 markedly suppressed the proliferative, migratory and invasive capacities of BCa cells. MeRIP-PCR and dual-luciferase report assays indicated that METTL3 could bind to the m6A sites of RRAS mRNA and suppress the transcriptional activity of RRAS. YTHDF2 could recognize the m6A sites of RRAS and mediate RRAS degradation. On the whole, the findings of the present study reveal the pivotal role of METTL3-catalyzed m6A modification in BCa tumorigenesis and development. The change could facilitate BCa tumor growth and metastasis by suppressing RRAS expression in an m6A YTHDF2-dependent manner. Targeting the METTL3/RRAS/YTHDF2 regulatory axis may thus prove to be a promising strategy for the diagnosis and therapy of BCa.

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“…Increased YTHDF2 expression in alveolar macrophages of early hypoxic stage mouse PH model was found which exacerbated PH and pulmonary vascular remodeling. The underlying mechanism involved the promotion of macrophage polarization and oxidative stress, mediated by increased degradation of heme oxygenase 1 ( Hmox1 ) mRNA [55]. Overall, m6A modification may be a target for the treatment of macrophage-mediated inflammatory diseases.…”

Section: M6a Modification In Monocytes/macrophagesmentioning

confidence: 99%

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

Teng,

Yi,

Chen

et al. 2023

J Innate Immun

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The post-transcriptional N6-methyladenosine (m6A) modification of RNA influences stability, transport, and translation with implications for various physiological and pathological processes. Immune cell development, differentiation, and activation are also thought to be regulated by m6A and affect host defense against pathogens and inflammatory response with impacts on infectious, neoplastic, autoimmune, cardiovascular, hepatic, and osteal diseases. The current review summarizes recent research on m6A in monocyte/macrophages, neutrophils, dendritic cells, natural killer cells, and microglia and gives insights into epigenetic modifications of the immune system and novel therapeutic strategies for immune-related diseases.

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Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages

Cited by 21 publications

References 53 publications

Development of a novel humanized mouse model to study bronchopulmonary dysplasia

Development of a novel humanized mouse model to study bronchopulmonary dysplasia

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

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