Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Chen, Wei; Zhang, Xuyao; Fan, Jiajun; Zai, Wenjing; Luan, Jingyun; Li, Yubin; Wang, Shaofei; Chen, Qicheng; Wang, Yichen; Liang, Yanxu; Ju, Dianwen

doi:10.7150/thno.20955

Cited by 43 publications

(41 citation statements)

References 52 publications

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“…It is well known that there are complex networks among AKT, JNK and ERK pathways in biological process. For example, Wu et al reported that IL-22 tethered to apolipoprotein A-I could ameliorate acute liver injury by altering EKT and AKT signaling transductions [40], suggesting the complicated connection among these pathways in liver injury. Moreover, in our previous work, we also found that miR-7 could affect the development of ALI, accompanied with altered transduction of AKT and ERK pathways [17].…”

Section: Discussionmentioning

confidence: 99%

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Mao

Zhou

et al. 2020

Preprint

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BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. MAPK4, a member of atypical MAPK family, has been implicated in the development of cancer. Herein, the current study aimed to investigate the possible role of MAPK4 in the pathology of ALI to identify potential candidates for ALI therapy. MethodsMurine ALI model was established in WT or MAPK4 -/mice and the expressions of MAPK4 were measured. The survival ratio of ALI model mice was observed. Moreover, the changes of pathologic injury and infiltration of inflammatory cells, as well as the related signaling pathways, in lung tissues were analyzed. Furthermore, the possible molecular mechanism of MAPK4 expression in ALI was analyzed by massARRAY and EMSA assay. Finally, the effect of MAPK4 silencing using shRNA interference on the pathology of ALI was identified. the expression of MAPK4 by binding to the core sequence of MAPK4 promoter. Importantly, MAPK4-shRNA treatment could significantly reduce the pathology of lung tissues and prolong survival time of ALI mice. Altogether, our study reveals an unknown role of MAPK4 in the pathology of ALI, indicating that MAPK4 might be a new therapeutic target for clinic therapy against ALI. Materials And MethodsMice MAPK4 deficiency (MAPK4 -/-) mice breeding pair in a C57BL/6 background were purchased from The Jackson Laboratory (027666). Animals were housed under specific pathogen-free conditions at Zunyi Medical University. Cell cultureRaw264.7 cells were purchased from Conservation Genetics CAS Kunming Cell Bank (KCB200603YJ), and were cultured in high glucose DEME containing 10% fetal bovine serum at 37°C in 5% CO 2 . Establishment of ALI ModelWT and MAPK4 -/mice (7 to 9 week-old) were challenged with i.p. injection of 10mg/kg LPS (Escherichia coli 0111:B4; Sigma) dissolved in sterile PBS as shown in our previous study [17]. Then the body weight and lung weight index (lung weight/body weight) was detected at indicated time. Bronchoalveolar LavageImmediately after euthanasia, 1 ml aliquots of PBS were slowly infused in the murine lungs through the tracheostomy and then withdrawn gently. This lavage was repeated three times using the same syringe. The collected lavage fluid was stored in a 10ml tube on ice. The fluid was centrifuged at 1000rpm and 4°C for 10 min, and the cell sediment was washed with PBS. The cell-free supernatant was centrifuged again at 14,000g and 4°C for 10 min, stored at −80°C and used for determination of cytokines content via ELISA. To the pellet, red blood lysis buffer (Solarbio, R1010) were used for 15 min and washed with PBS. Next, the pellet was resuspended for analysis. Lung edema determinationLungs from mice were excised and completely dried in the oven at 60°C 24h for calculation of lung wet/dry ratio.

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Section: Discussionmentioning

confidence: 99%

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Mao

Zhou

et al. 2020

Preprint

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“…It is well known that there are complex networks among AKT, JNK and ERK pathways in biological process. For example, Chen et al reported that IL-22 tethered to apolipoprotein A-I could ameliorate acute liver injury by altering EKT and AKT signaling transductions [37], suggesting the complicated connection among these pathways in liver injury. Moreover, in our previous work, we also found that miR-7 could affect the development of ALI, accompanied with altered transduction of AKT and ERK pathways [15].…”

Section: Discussionmentioning

confidence: 99%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

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“…Our animal experimental procedures were carried out following the protocols evaluated and approved by the Animal Care and Use Ethics Committee of School of Pharmacy, Fudan University. Immunohistochemical staining, measurement of mitochondrial membrane potential, histological and ROS staining of kidney sections were performed as previously described [22][23][24].…”

Section: Animal Modelsmentioning

confidence: 99%

“…Kidney cells were grown and treated as described above. MitoSOX (mitochondrial ROS), MitoTracker Green (total mitochondrial mass) and MitoTracker Red (mitochondrial membrane potential) staining were carried out according to the manufacturer's instructions and previous researches [22][23][24]. We obtained the results by the Beckman Coulter Flow Cytometer and the CytExpert software (BD Biosciences, USA).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Mechanistically, increased glycolysis and oxidative phosphorylation (OXPHOS) can promote growth and defensive signaling pathways or can supply the higher energetic demands of mitosis and anabolic biosynthesis during organ repair [19][20][21]. Recently, our studies have demonstrated that IL-22 alleviates mitochondrial dysfunction in liver, which involves the cellular metabolic processes [22][23][24]. Thus, we asked whether IL-22 protects against TECs damage and apoptosis via regulating their metabolic states.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

Chen

Shen

Fan

et al. 2020

Preprint

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Kidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

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Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

Cited by 43 publications

References 52 publications

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

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