Akt1 regulates pulmonary fibrosis via modulating IL-13 expression in macrophages

Nie, Yunjuan; Hu, Yudong; Yu, Kaikai; Zhang, Dan; Shi, Yin-Ze; Li, Yaolin; Sun, Lei; Qian, Feng

doi:10.1177/1753425919861774

Cited by 25 publications

(19 citation statements)

References 47 publications

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“…Akt1, a pro‐survival kinase, is known to mediate mitochondrial H2O2 generation. Akt1 activation is strongly associated with regulating survival and many fibrotic remodelling processes . The phosphorylation level of Akt is associated with HSC proliferation and collagen I expression .…”

Section: Discussionmentioning

confidence: 99%

TIM‐4 interference in Kupffer cells against CCL4‐induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway

Chen

Wang

et al. 2019

Cell Proliferation

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Objectives T‐cell immunoglobulin domain and mucin domain‐4 (TIM‐4) is selectively expressed on antigen‐presenting cells (APCs) and modulates various immune responses. However, the role of TIM‐4 expressed by Kupffer cells (KCs) in liver fibrosis remains unclear. The present study aimed to explore whether and how TIM‐4 expressed by KCs is involved in liver fibrosis. Materials and Methods Mice chronic liver fibrosis models were established and divided into the olive‐induced control group, CCL4‐induced control group, olive‐induced TIM‐4 interference group and CCL4‐induced TIM‐4 interference group. Different techniques were used to monitor the fibrotic effects of TIM‐4, including histopathological assays, Western blotting, ELISA and transmission electron microscopy. Additionally, mice liver transplant models were established to determine the fibrotic effects of TIM‐4 on fibrosis after liver transplantation (LT). Results We found that the induction of liver fibrosis by CCL4 was associated with TIM‐4 expression in KCs. TIM‐4 interference essentially contributed to liver fibrosis resolution. KCs from the TIM‐4 interference group had decreased levels of pro‐fibrotic markers, reduced TGF‐β1 secretion and inhibited hepatic stellate cell (HSC) differentiation into myofibroblast‐like cells. In addition, we used GdCl3 to verify that KCs are the primary source of TGF‐β1 during fibrosis progression. Moreover, KCs from CCL4‐induced mice showed increased ROS production, mitophagy activation and TGF‐β1 secretion. However, TIM‐4 interference in the KCs inhibited Akt1‐mediated ROS production, resulting in the suppression of PINK1, Parkin and LC3‐II/I activation and the reduction of TGF‐β1 secretion during liver fibrosis. Additionally, TIM‐4 interference potentially attenuated development of fibrosis after LT. Conclusions Our findings revealed the underlying mechanisms of TIM‐4 interference in KCs to mitigate liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

TIM‐4 interference in Kupffer cells against CCL4‐induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway

Chen

Wang

et al. 2019

Cell Proliferation

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“…Studies have shown that IL-13 produced by M2 macrophages also plays a key role in the homeostasis control of normal lungs and the pathogenesis of pulmonary fibrosis. AKT1 regulates pulmonary fibrosis by inducing M2 macrophages to produce IL-13, suggesting that targeting AKT1 blocks the fibrotic process of IPF 95 . The O subclasses of the Forkhead box (FOXO) family, such as FOXO1, FOXO3, and FOXO4, are directly phosphorylated by AKT, causing them to be exported to the cytoplasm and degraded through the ubiquitin-proteasome pathway.…”

Section: Pi3k/akt Signaling In Different Development Stage Of Ipfmentioning

confidence: 99%

Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

Wang

Cai

et al. 2022

Acta Pharmaceutica Sinica B

169

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

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“…A previous study indicated that m 6 A mRNA methylation regulates AKT1 activity, which promotes the tumorigenicity of endometrial cancer (46). Protein kinase B (AKT) is a pleckstrin homology (PH) domain comprising a serine threonine kinase (53). AKT1 is an important isoform of AKT, which acts as a vital subtype and is closely related to many types of human tumors (54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer

Shi¹,

Gong²,

Zhuo³

et al. 2022

Ann Transl Med

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Background: Treatments for non-small cell lung cancer (NSCLC) have improved tremendously, but therapeutic resistance is a common and major clinical challenge in treatment. Methyltransferase-like 3 (METTL3) is a ribonucleic acid (RNA) methyltransferase that has crucial functions in the development and progression of cancers, including drug resistance, by regulating N6-methyladenosine (m 6 A) modification.However, the role of METTL3 in the progression and drug resistance of NSCLC is poorly understood. Methods:The expression levels of METTL3 and AKT serine/threonine kinase 1 (AKT1) in NSCLC tissues were detected using quantitative real-time PCR (RT-qPCR), Western blots, and immunohistochemical assays. The m 6 A levels of AKT1 messenger RNA (mRNA) in NSCLC tissues were detected using m 6 A methylated RNA immunoprecipitation-quantitative polymerase chain reaction. Results:The expression levels of METTL3 and the AKT1 protein were significantly increased in NSCLC tissues, and m6A expression levels of AKT1 mRNA were dramatically upregulated in NSCLC tissues. Additionally, METTL3, AKT1 protein, and m 6 A levels of AKT1 mRNA were overexpressed in chemoresistant NSCLC samples, and high expression levels of METTL3 and AKT1 were correlated with poor patient survival, especially in chemoresistant NSCLC patients. Further, AKT1 protein expression and m 6 A levels of AKT1 mRNA were positively correlated with METTL3 expression, and AKT1 protein expression was positively correlated with m 6 A levels of AKT1 mRNA. Moreover, METTL3 and AKT1 protein expression levels were significantly associated with cisplatin susceptibility, tumor, node, metastasis stage, and lymph node metastasis.Conclusions: Taken together, our results indicate that METTL3 contributes to the progression and chemoresistance of NSCLC by promoting AKT1 protein expression through regulating AKT1 mRNA m6A levels, and may provide an efficient therapeutic intervention target for overcoming chemoresistance in NSCLC.

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Akt1 regulates pulmonary fibrosis via modulating IL-13 expression in macrophages

Cited by 25 publications

References 47 publications

TIM‐4 interference in Kupffer cells against CCL4‐induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway

TIM‐4 interference in Kupffer cells against CCL4‐induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway

Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer

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