DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway
Alcohol-induced liver injury (ALI) is associated with inflammatory responses regulated by macrophages. Activation of macrophages plays a crucial role in ALI while DNA methylation-regulated gene silencing is associated with inflammation processes in macrophages. Proline-Serine-Threonine Phosphatase I...
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| Format: | Article |
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Elsevier
2022-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661822000706 |
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| author | Jie-Jie Xu Lin Zhu Hai-Di Li Xiao-Sa Du Juan-Juan Li Na-Na Yin Xiao-Ming Meng Cheng Huang Jun Li |
| author_facet | Jie-Jie Xu Lin Zhu Hai-Di Li Xiao-Sa Du Juan-Juan Li Na-Na Yin Xiao-Ming Meng Cheng Huang Jun Li |
| author_sort | Jie-Jie Xu |
| collection | DOAJ |
| description | Alcohol-induced liver injury (ALI) is associated with inflammatory responses regulated by macrophages. Activation of macrophages plays a crucial role in ALI while DNA methylation-regulated gene silencing is associated with inflammation processes in macrophages. Proline-Serine-Threonine Phosphatase Interacting Protein 2 (PSTPIP2), which belongs to the Fes/CIP4 homology-Bin/Amphiphysin/Rvs domain family of proteins and plays a role in macrophages. Previous studies have shown that Pstpip2 can be methylated. Herein, its expression was found to be significantly downregulated in primary liver macrophages isolated from EtOH-fed mice and EtOH-induced RAW264.7 cells. Overexpression of PSTPIP2 using liver-specific recombinant AAV serotype 9 (rAAV9)-PSTPIP2 in EtOH-fed mice dramatically alleviated liver injury and inflammatory responses. In addition, silencing of PSTPIP2 aggravated the alcohol-induced inflammatory response in vitro. Mechanistically, PSTPIP2 might affect macrophage-induced inflammatory responses by regulating the STAT1 and NF-κB signaling pathways. The downregulation of PSTPIP2 in ALI may be associated with DNA methylation. Methylation-specific PCR and western blotting analyses showed that EtOH induced abnormal DNA methylation patterns and increased the protein expression levels of DNMT1, DNMT3a, and DNMT3b. The chromatin immunoprecipitation assay showed that DNMT3a could directly bind to the Pstpip2 promoter and act as a principal regulator of PSTPIP2 expression. Moreover, silencing of DNMT3a significantly restored the EtOH-induced low expression of PSTPIP2 and inhibited EtOH-induced inflammation. Overall, these findings provide a detailed understanding of the possible functions and mechanisms of PSTPIP2 in ALI, thus providing new substantive research to elucidate the pathogenesis of ALI and investigate potential targeted treatment strategies. |
| first_indexed | 2024-03-08T17:06:28Z |
| format | Article |
| id | doaj.art-00c9a3fad48b4846b7c954aefc9369f4 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-08T17:06:28Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-00c9a3fad48b4846b7c954aefc9369f42024-01-04T04:36:28ZengElsevierPharmacological Research1096-11862022-03-01177106125DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathwayJie-Jie Xu0Lin Zhu1Hai-Di Li2Xiao-Sa Du3Juan-Juan Li4Na-Na Yin5Xiao-Ming Meng6Cheng Huang7Jun Li8Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaCorrespondence to: School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; Hefei 230032, ChinaAlcohol-induced liver injury (ALI) is associated with inflammatory responses regulated by macrophages. Activation of macrophages plays a crucial role in ALI while DNA methylation-regulated gene silencing is associated with inflammation processes in macrophages. Proline-Serine-Threonine Phosphatase Interacting Protein 2 (PSTPIP2), which belongs to the Fes/CIP4 homology-Bin/Amphiphysin/Rvs domain family of proteins and plays a role in macrophages. Previous studies have shown that Pstpip2 can be methylated. Herein, its expression was found to be significantly downregulated in primary liver macrophages isolated from EtOH-fed mice and EtOH-induced RAW264.7 cells. Overexpression of PSTPIP2 using liver-specific recombinant AAV serotype 9 (rAAV9)-PSTPIP2 in EtOH-fed mice dramatically alleviated liver injury and inflammatory responses. In addition, silencing of PSTPIP2 aggravated the alcohol-induced inflammatory response in vitro. Mechanistically, PSTPIP2 might affect macrophage-induced inflammatory responses by regulating the STAT1 and NF-κB signaling pathways. The downregulation of PSTPIP2 in ALI may be associated with DNA methylation. Methylation-specific PCR and western blotting analyses showed that EtOH induced abnormal DNA methylation patterns and increased the protein expression levels of DNMT1, DNMT3a, and DNMT3b. The chromatin immunoprecipitation assay showed that DNMT3a could directly bind to the Pstpip2 promoter and act as a principal regulator of PSTPIP2 expression. Moreover, silencing of DNMT3a significantly restored the EtOH-induced low expression of PSTPIP2 and inhibited EtOH-induced inflammation. Overall, these findings provide a detailed understanding of the possible functions and mechanisms of PSTPIP2 in ALI, thus providing new substantive research to elucidate the pathogenesis of ALI and investigate potential targeted treatment strategies.http://www.sciencedirect.com/science/article/pii/S1043661822000706Alcohol-induced liver injury (ALI)Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2)InflammationSTAT1DNA methylation |
| spellingShingle | Jie-Jie Xu Lin Zhu Hai-Di Li Xiao-Sa Du Juan-Juan Li Na-Na Yin Xiao-Ming Meng Cheng Huang Jun Li DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway Pharmacological Research Alcohol-induced liver injury (ALI) Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) Inflammation STAT1 DNA methylation |
| title | DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway |
| title_full | DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway |
| title_fullStr | DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway |
| title_full_unstemmed | DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway |
| title_short | DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway |
| title_sort | dnmt3a mediated methylation of pstpip2 enhances inflammation in alcohol induced liver injury via regulating stat1 and nf κb pathway |
| topic | Alcohol-induced liver injury (ALI) Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) Inflammation STAT1 DNA methylation |
| url | http://www.sciencedirect.com/science/article/pii/S1043661822000706 |
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