Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model
Abstract Recent studies challenge the dogma that a 21-mer phosphopeptide P140 protects against direct cell damage in the phase-III clinical trial (NCT02504645) for lupus, involving reactive oxygen species (ROS)-dependent release of citrullinated histone H3 (H3cit)-linked neutrophil extracellular tra...
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| Format: | Article |
| Language: | English |
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Springer
2023-11-01
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| Series: | Molecular Biomedicine |
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| Online Access: | https://doi.org/10.1186/s43556-023-00149-9 |
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| author | Jianghong Zhong Chanyu Zheng Zhongheng Chen Hangqi Yue Haiqiang Gao Yunfan Jiang Hui Hui Jie Tian |
| author_facet | Jianghong Zhong Chanyu Zheng Zhongheng Chen Hangqi Yue Haiqiang Gao Yunfan Jiang Hui Hui Jie Tian |
| author_sort | Jianghong Zhong |
| collection | DOAJ |
| description | Abstract Recent studies challenge the dogma that a 21-mer phosphopeptide P140 protects against direct cell damage in the phase-III clinical trial (NCT02504645) for lupus, involving reactive oxygen species (ROS)-dependent release of citrullinated histone H3 (H3cit)-linked neutrophil extracellular traps. An open question is the cellular location of ROS production and H3cit formation in lupus. In this study, we examined the effects of P140 peptides on ROS production and H3cit location in lupus with in vivo and situ fluorescence imaging with subcellular resolution. We developed a mouse model of the B6 strain harbouring a bioluminescent reporter under the control of the Lysozyme M promoter. Based on the imiquimod-induced disease model of B6 mice, we used bioluminescent imaging, flow cytometry analysis, and immunohistology staining to study the effects of P140 peptides in lupus. We found a profound accumulation of CX3CR1-positive macrophages in the lungs of lupus mice after the application of P140, accompanied by lung fibrosis formation. The defined P140-mediated macrophage responses were associated with an increase of H3cit in the cytosol, interleukin-1 receptor type 1 on the extracellular membrane, and intracellular production of ROS. Of interest, the disease of imiquimod-induced lupus was prevented with an antioxidant drug apocynin. This study shows that P140 peptides play a role in aggravated murine lupus in a manner dependent on ROS production and H3cit upregulation through pulmonary macrophages. |
| first_indexed | 2024-03-11T12:44:27Z |
| format | Article |
| id | doaj.art-267c85d1bac14f20941af5a17db79ccf |
| institution | Directory Open Access Journal |
| issn | 2662-8651 |
| language | English |
| last_indexed | 2024-03-11T12:44:27Z |
| publishDate | 2023-11-01 |
| publisher | Springer |
| record_format | Article |
| series | Molecular Biomedicine |
| spelling | doaj.art-267c85d1bac14f20941af5a17db79ccf2023-11-05T12:05:19ZengSpringerMolecular Biomedicine2662-86512023-11-014111210.1186/s43556-023-00149-9Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus modelJianghong Zhong0Chanyu Zheng1Zhongheng Chen2Hangqi Yue3Haiqiang Gao4Yunfan Jiang5Hui Hui6Jie Tian7School of Engineering Medicine, Beihang University, Beihang UniversitySchool of Biological Science and Medical Engineering, Beihang UniversitySchool of Biological Science and Medical Engineering, Beihang UniversitySchool of Biological Science and Medical Engineering, Beihang UniversitySchool of Biological Science and Medical Engineering, Beihang UniversitySchool of Biological Science and Medical Engineering, Beihang UniversityCAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of SciencesSchool of Engineering Medicine, Beihang University, Beihang UniversityAbstract Recent studies challenge the dogma that a 21-mer phosphopeptide P140 protects against direct cell damage in the phase-III clinical trial (NCT02504645) for lupus, involving reactive oxygen species (ROS)-dependent release of citrullinated histone H3 (H3cit)-linked neutrophil extracellular traps. An open question is the cellular location of ROS production and H3cit formation in lupus. In this study, we examined the effects of P140 peptides on ROS production and H3cit location in lupus with in vivo and situ fluorescence imaging with subcellular resolution. We developed a mouse model of the B6 strain harbouring a bioluminescent reporter under the control of the Lysozyme M promoter. Based on the imiquimod-induced disease model of B6 mice, we used bioluminescent imaging, flow cytometry analysis, and immunohistology staining to study the effects of P140 peptides in lupus. We found a profound accumulation of CX3CR1-positive macrophages in the lungs of lupus mice after the application of P140, accompanied by lung fibrosis formation. The defined P140-mediated macrophage responses were associated with an increase of H3cit in the cytosol, interleukin-1 receptor type 1 on the extracellular membrane, and intracellular production of ROS. Of interest, the disease of imiquimod-induced lupus was prevented with an antioxidant drug apocynin. This study shows that P140 peptides play a role in aggravated murine lupus in a manner dependent on ROS production and H3cit upregulation through pulmonary macrophages.https://doi.org/10.1186/s43556-023-00149-9LupusROSH3citNeutrophilsMacrophages |
| spellingShingle | Jianghong Zhong Chanyu Zheng Zhongheng Chen Hangqi Yue Haiqiang Gao Yunfan Jiang Hui Hui Jie Tian Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model Molecular Biomedicine Lupus ROS H3cit Neutrophils Macrophages |
| title | Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model |
| title_full | Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model |
| title_fullStr | Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model |
| title_full_unstemmed | Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model |
| title_short | Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model |
| title_sort | phosphopeptides p140 cause oxidative burst responses of pulmonary macrophages in an imiquimod induced lupus model |
| topic | Lupus ROS H3cit Neutrophils Macrophages |
| url | https://doi.org/10.1186/s43556-023-00149-9 |
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