Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance

Itakura, Junya; Sato, Miwa; Ito, Toshihiro; Mino, Michinobu; Fushimi, Soichiro; Takahashi, Sakuma; Yoshimura, Teizo; Matsukawa, Akihiro

doi:10.1038/s41598-017-13204-7

Cited by 17 publications

(12 citation statements)

References 44 publications

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“…METTL3 depletion attenuated the translation of SPRED2 mediated by YTHDF1. Previous studies have shown that Spred2 -knockout mice have more infiltrating macrophages with an M1 phenotype in mesenteric white adipose tissue 41 and produce significantly higher levels of inflammatory cytokines 42 , which seems to partly differ from our results. The results also indicate that the dynamic plasticity of macrophages is regulated by the local microenvironment, which makes it possible to target macrophages for disease therapy.…”

Section: Discussioncontrasting

confidence: 99%

RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

et al. 2021

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N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.

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Section: Discussioncontrasting

confidence: 99%

RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

et al. 2021

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“…The TLR4 ligand LPS stimulated bone marrow-derived macrophages to produce TNFα and MCP-1 (17). We recently showed that macrophage cytokine response to LPS was partially blocked by U0126 (24), suggesting that Spred2 may be involved in the regulation of the MAPK pathway downstream of TLR4. It is also possible that Spred2 may suppress TLR signaling by other unidentified mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…As the ERK/MAPK pathway is involved in several cellular processes in adipocytes or macrophages, dysregulation of ERK/MAPK signaling could affect diet-induced obesity and obesity-induced adipose tissue inflammation and metabolic abnormalities. We previously reported that Spred2-deficiency in mice exacerbated acetaminophen-induced hepatotoxicity (23), LPS-induced acute lung inflammation (17), D-galactosamine/LPS-induced acute liver injury (18), and polymicrobial septic peritonitis (24). In the present study, we demonstrate, for the first time, that Spred2 plays an important role in regulating the development of diet-induced obesity, obesity-induced adipose tissue inflammation, and metabolic abnormalities, including fatty liver disease.…”

Section: Introductionmentioning

confidence: 99%

Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

et al. 2019

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Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.

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“…We previously demonstrated that the production of proinflammatory mediators was up-regulated in Spred2 −/− resident or M-CSF-induced BM-derived macrophages 22 , 23 . Here, we examined the production of TNFα and MCP-1 by inflammatory macrophages obtained by intraperitoneal injection of thioglycolate (TG) in response to BLM or LPS.…”

Section: Resultsmentioning

confidence: 99%

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

Kawara

Mizuta

Fujisawa

et al. 2020

Sci Rep

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The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

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Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance

Cited by 17 publications

References 44 publications

RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

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