Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway
CXC chemokine receptor 2 (CXCR2) plays an important role in demyelinating diseases, but the detailed mechanisms were not yet clarified. In the present study, we mainly investigated the critical function and the potential molecular mechanisms of CXCR2 on oligodendrocyte precursor cell (OPC) different...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123000025 |
| _version_ | 1828053163666571264 |
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| author | Cheng Ju Fangyu Yuan Lu Wang Caixia Zang Jingwen Ning Meiyu Shang Jingwei Ma Gen Li Yang Yang Qiuzhu Chen Yueqi Jiang Fangfang Li Xiuqi Bao Dan Zhang |
| author_facet | Cheng Ju Fangyu Yuan Lu Wang Caixia Zang Jingwen Ning Meiyu Shang Jingwei Ma Gen Li Yang Yang Qiuzhu Chen Yueqi Jiang Fangfang Li Xiuqi Bao Dan Zhang |
| author_sort | Cheng Ju |
| collection | DOAJ |
| description | CXC chemokine receptor 2 (CXCR2) plays an important role in demyelinating diseases, but the detailed mechanisms were not yet clarified. In the present study, we mainly investigated the critical function and the potential molecular mechanisms of CXCR2 on oligodendrocyte precursor cell (OPC) differentiation and remyelination. The present study demonstrated that inhibiting CXCR2 significantly enhanced OPC differentiation and remyelination in primary cultured OPCs and ethidium bromide (EB)-intoxicated rats by facilitating the formation of myelin proteins, including PDGFRα, MBP, MAG, MOG, and Caspr. Further investigation identified phosphodiesterase 10A (PDE10A) as a main downstream protein of CXCR2, interacting with the receptor to regulate OPC differentiation, in that inhibition of CXCR2 reduced PDE10A expression while suppression of PDE10A did not affect CXCR2. Furthermore, inhibition of PDE10A promoted OPC differentiation, whereas overexpression of PDE10A down-regulated OPC differentiation. Our data also revealed that inhibition of CXCR2/PDE10A activated the cAMP/ERK1/2 signaling pathway, and up-regulated the expression of key transcription factors, including SOX10, OLIG2, MYRF, and ZFP24, that ultimately promoted remyelination and myelin protein biosynthesis. In conclusion, our findings suggested that inhibition of CXCR2 promoted OPC differentiation and enhanced remyelination by regulating PDE10A/cAMP/ERK1/2 signaling pathway. The present data also highlighted that CXCR2 may serve as a potential target for the treatment of demyelination diseases. |
| first_indexed | 2024-04-10T20:02:22Z |
| format | Article |
| id | doaj.art-455bfa5369e747b894c8870f3c0b3ba8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-10T20:02:22Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-455bfa5369e747b894c8870f3c0b3ba82023-01-27T04:18:27ZengElsevierNeurobiology of Disease1095-953X2023-02-01177105988Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathwayCheng Ju0Fangyu Yuan1Lu Wang2Caixia Zang3Jingwen Ning4Meiyu Shang5Jingwei Ma6Gen Li7Yang Yang8Qiuzhu Chen9Yueqi Jiang10Fangfang Li11Xiuqi Bao12Dan Zhang13State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaState Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaCorresponding author.; State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, ChinaCXC chemokine receptor 2 (CXCR2) plays an important role in demyelinating diseases, but the detailed mechanisms were not yet clarified. In the present study, we mainly investigated the critical function and the potential molecular mechanisms of CXCR2 on oligodendrocyte precursor cell (OPC) differentiation and remyelination. The present study demonstrated that inhibiting CXCR2 significantly enhanced OPC differentiation and remyelination in primary cultured OPCs and ethidium bromide (EB)-intoxicated rats by facilitating the formation of myelin proteins, including PDGFRα, MBP, MAG, MOG, and Caspr. Further investigation identified phosphodiesterase 10A (PDE10A) as a main downstream protein of CXCR2, interacting with the receptor to regulate OPC differentiation, in that inhibition of CXCR2 reduced PDE10A expression while suppression of PDE10A did not affect CXCR2. Furthermore, inhibition of PDE10A promoted OPC differentiation, whereas overexpression of PDE10A down-regulated OPC differentiation. Our data also revealed that inhibition of CXCR2/PDE10A activated the cAMP/ERK1/2 signaling pathway, and up-regulated the expression of key transcription factors, including SOX10, OLIG2, MYRF, and ZFP24, that ultimately promoted remyelination and myelin protein biosynthesis. In conclusion, our findings suggested that inhibition of CXCR2 promoted OPC differentiation and enhanced remyelination by regulating PDE10A/cAMP/ERK1/2 signaling pathway. The present data also highlighted that CXCR2 may serve as a potential target for the treatment of demyelination diseases.http://www.sciencedirect.com/science/article/pii/S0969996123000025CXC chemokine receptor 2OligodendrocytesRemyelinationPhosphodiesterase 10AEthidium bromide |
| spellingShingle | Cheng Ju Fangyu Yuan Lu Wang Caixia Zang Jingwen Ning Meiyu Shang Jingwei Ma Gen Li Yang Yang Qiuzhu Chen Yueqi Jiang Fangfang Li Xiuqi Bao Dan Zhang Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway Neurobiology of Disease CXC chemokine receptor 2 Oligodendrocytes Remyelination Phosphodiesterase 10A Ethidium bromide |
| title | Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway |
| title_full | Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway |
| title_fullStr | Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway |
| title_full_unstemmed | Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway |
| title_short | Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway |
| title_sort | inhibition of cxcr2 enhances cns remyelination via modulating pde10a camp signaling pathway |
| topic | CXC chemokine receptor 2 Oligodendrocytes Remyelination Phosphodiesterase 10A Ethidium bromide |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123000025 |
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